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Atherosclerosis: Endothelial Dysfunction and Beyond
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Atherosclerosis: Endothelial Dysfunction and Beyond

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Vascular Medicine".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 62108

Special Issue Editors

Prof. Dr. Andrzej Surdacki

E-Mail Website
Guest Editor
Second Department of Cardiology, Jagiellonian University Medical College, 2 Jakubowskiego Street, 30-688 Krakow, Poland
Interests: endothelial dysfunction; nitric oxide; asymmetric dimethylarginine; homoarginine; coronary artery disease; atherogenesis; nontraditional cardiovascular risk factors; chronic kidney disease; cardionephrology; metabolic syndrome; insulin resistance; cardiodiabetology; cardiooncology; adult childhood cancer survivors; cardiorheumatology; echocardiography; aortic valve stenosis; myocardial hemodynamics; left ventricular hypertrophy; diastolic dysfunction; heart failure with preserved ejection fraction; arterial compliance; platelet reactivity; antiplatelet drugs; proton pump inhibitors
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Dimitrios Tsikas

E-Mail Website
Guest Editor
Institute of Toxicology, Core Unit Proteomics, Hannover Medical School, Hannover, Germany
Interests: nitric oxide; asymmetric dimethylarginine; homoarginine; oxidative stress; gas chromatography−mass spectrometry; bioanalytical methods development; high-performance liquid chromatography

Special Issue Information

Dear Colleagues,

Endothelial dysfunction, a recognized antecedent of atherosclerotic plaques, is associated with reduced bioavailability of nitric oxide (NO), a key endogenous anti-atherogenic molecule. The magnitude of endothelial dysfunction predicts future adverse cardiovascular events both in the general population and patients with risk factors or atherosclerotic cardiovascular (CV) disease. Beyond direct effects within the vessel wall, the L-arginine-NO pathway modulates the activity of pathophysiologic contributors to acute coronary syndromes and stroke, i.e., platelets, the coagulation and fibrinolytic pathways, and the immune system. Additionally, impaired NO bioavailability accelerates adverse CV remodelling in aging, hypertension, diabetes, and heart failure. Recent years have witnessed expanding research on the role of NO and other endothelial mediators in a variety of common disorders, including metabolic syndrome, chronic kidney disease, and heart failure with preserved ejection fraction. Moreover, improved endothelial function may be implicated in beneficial pleiotropic effects of new antidiabetic, antiplatelet, and anticoagulant drugs. On the other hand, there is no consensus with regard to the utility of particular endothelial biomarkers in specific clinical settings. With this Special Issue, we hope to encourage submissions of original articles and reviews covering novel aspects of atherogenesis and endothelial dysfunction, with a focus on emerging CV risk factors, the L-arginine-NO system, and related metabolic pathways.

We look forward to receiving your submission.

Prof. Dr. Andrzej Surdacki
Prof. Dr. Dimitrios Tsikas
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • Endothelial dysfunction
  • L-arginine-nitric oxide pathway and related metabolites
  • Aging
  • Platelets
  • Metabolic syndrome and diabetes
  • Chronic kidney disease
  • Heart failure
  • Pleiotropic effects of cardiovascular drugs

Published Papers (21 papers)

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17 pages, 2308 KiB  
Article
Diminished Systemic Amino Acids Metabolome and Lipid Peroxidation in Ureteropelvic Junction Obstruction (UPJO) Infants Requiring Surgery
by Olga Begou, Antigoni Pavlaki, Olga Deda, Alexander Bollenbach, Kathrin Drabert, Helen Gika, Evangelia Farmaki, John Dotis, Nikoleta Printza, Georgios Theodoridis and Dimitrios Tsikas
J. Clin. Med. 2021, 10(7), 1467; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10071467 - 02 Apr 2021
Cited by 3 | Viewed by 1829
Abstract
Congenital anomalies of the urinary tract, and particularly of obstructive nephropathy such as ureteropelvic junction obstruction (UPJO) in infants, can later lead to chronic kidney disease and hypertension. Fundamental questions regarding underlying mechanisms remain unanswered. The aim of the present study was to [...] Read more.
Congenital anomalies of the urinary tract, and particularly of obstructive nephropathy such as ureteropelvic junction obstruction (UPJO) in infants, can later lead to chronic kidney disease and hypertension. Fundamental questions regarding underlying mechanisms remain unanswered. The aim of the present study was to quantitate the systemic amino acids metabolome in 21 UPJO infants requiring surgery (Group A) and 21 UPJO infants under conservative treatment (Group B). Nineteen healthy age-matched infants served as controls (Group C). Serum amino acids involved in several pathways and representative metabolites, including the L-arginine-derived nitric oxide (NO) metabolites nitrite and nitrate and the lipid peroxidation biomarker malondialdehyde (MDA) were measured by gas chromatography–mass spectrometry (GC–MS) methods using their stable-isotope labeled analogs as internal standards after derivatization to their methyl esters N-pentafluoropropionic amides (amino acids) and to their pentafluorobenzyl derivatives (nitrite, nitrate, MDA). The concentrations of the majority of the biomarkers were found to be lower in Group A compared to Group B. Statistical analysis revealed clear differentiation between the examined study groups. Univariate statistical analysis highlighted serum homoarginine (q = 0.006), asymmetric dimethylarginine (q = 0.05) and malondialdehyde (q = 0.022) as potential biomarkers for UPJO infants requiring surgery. Group A also differed from Group B with respect to the diameter of the preoperative anterior–posterior renal pelvis (AP) as well as regarding the number and extent of inverse correlations between AP and the serum concentrations of the biomarkers. In Group A, but not in Group B, the AP diameter strongly correlated with hydroxy-proline (r = −0.746, p = 0.0002) and MDA (r = −0.754, p = 0.002). Our results indicate a diminished amino acids metabolome in the serum of UPJO infants requiring surgery comparing to a conservative group. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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12 pages, 4874 KiB  
Article
NO Synthesis Markers Are Not Significantly Associated with Blood Pressure and Endothelial Dysfunction in Patients with Arterial Hypertension: A Cross-Sectional Study
by Oliver Malle, Christian Trummer, Verena Theiler-Schwetz, Andreas Meinitzer, Martin H. Keppel, Martin R. Grübler, Andreas Tomaschitz, Jakob Voelkl, Winfried März and Stefan Pilz
J. Clin. Med. 2020, 9(12), 3895; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9123895 - 30 Nov 2020
Cited by 3 | Viewed by 1514
Abstract
Nitric oxide (NO) synthesis markers, comprising L-homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), are significantly associated with cardiovascular events and mortality. Being involved in NO pathways, they may be of high importance regulating vascular tone and arterial hypertension, but data on this [...] Read more.
Nitric oxide (NO) synthesis markers, comprising L-homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), are significantly associated with cardiovascular events and mortality. Being involved in NO pathways, they may be of high importance regulating vascular tone and arterial hypertension, but data on this topic are sparse and controversial. In this study, we evaluated whether these NO synthesis markers are associated with blood pressure values and pulse wave velocity (PWV). This analysis was based on the data of the Styrian Vitamin D Hypertension Trial, which included adults with arterial hypertension. We analyzed correlations of NO synthesis markers with 24 h ambulatory blood pressure values and PWV (primary outcomes), as well as with anthropometric and laboratory data. A total of 509 patients were included in the present analysis. The mean age was 61.2 ± 10.5 years, mean PWV was 8.6 ± 2.4 m/s, mean 24 h systolic blood pressure was 127.5 ± 13.8 mmHg and mean 24 h diastolic blood pressure was 76.4 ± 9.5 mmHg. In bivariate analyses, there was a significant positive correlation between homoarginine and 24 h diastolic blood pressure (r = 0.1; p = 0.02), which was revealed to be no longer significant after adjustment for age, gender and glomerular filtration rate (GFR) in multivariate regression analysis. No other significant correlations of any NO synthesis markers with blood pressure or PWV were observed. In line with previous studies, there were inverse associations between homoarginine and age and between ADMA or SDMA and GFR (p < 0.05 for all). This study did not reveal a significant association between homoarginine, ADMA or SDMA and blood pressure or PWV in hypertensive adults. These results suggested that the associations of these parameters with adverse outcome may not be mediated by hypertension and/or endothelial dysfunction. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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19 pages, 1015 KiB  
Article
Local and Systemic Alterations of the L-Arginine/Nitric Oxide Pathway in Sputum, Blood, and Urine of Pediatric Cystic Fibrosis Patients and Effects of Antibiotic Treatment
by Beatrice Hanusch, Folke Brinkmann, Sebene Mayorandan, Kristine Chobanyan-Jürgens, Anna Wiemers, Kathrin Jansen, Manfred Ballmann, Anjona Schmidt-Choudhury, Alexander Bollenbach, Nico Derichs, Dimitrios Tsikas and Thomas Lücke
J. Clin. Med. 2020, 9(12), 3802; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9123802 - 24 Nov 2020
Cited by 7 | Viewed by 1898
Abstract
Alterations in the L-arginine (Arg)/nitric oxide (NO) pathway have been reported in cystic fibrosis (CF; OMIM 219700) as the result of various factors including systemic and local inflammatory activity in the airways. The aim of the present study was to evaluate the Arg/NO [...] Read more.
Alterations in the L-arginine (Arg)/nitric oxide (NO) pathway have been reported in cystic fibrosis (CF; OMIM 219700) as the result of various factors including systemic and local inflammatory activity in the airways. The aim of the present study was to evaluate the Arg/NO metabolism in pediatric CF patients with special emphasis on lung impairment and antibiotic treatment. Seventy CF patients and 78 healthy controls were included in the study. CF patients (43% male, median age 11.8 years) showed moderately impaired lung functions (FEV1 90.5 ± 19.1% (mean ± SD); 21 (30%) had a chronic Pseudomonas aeruginosa (PSA) infection, and 24 (33%) had an acute exacerbation). Plasma, urinary, and sputum concentrations of the main Arg/NO metabolites, nitrate, nitrite, Arg, homoarginine (hArg), and asymmetric dimethylarginine (ADMA) were determined in pediatric CF patients and in healthy age-matched controls. Clinical parameters in CF patients included lung function and infection with PSA. Additionally, the Arg/NO pathway in sputum samples of five CF patients was analyzed before and after routine antibiotic therapy. CF patients with low fractionally exhaled NO (FENO) showed lower plasma Arg and nitrate concentrations. During acute exacerbation, sputum Arg and hArg levels were high and dropped after antibiotic treatment: Arg: pre-antibiotics: 4.14 nmol/25 mg sputum vs. post-antibiotics: 2.33 nmol/25 mg sputum, p = 0.008; hArg: pre-antibiotics: 0.042 nmol/25 mg sputum vs. post-antibiotics: 0.029 nmol/25 mg sputum, p = 0.035. The activated Arg/NO metabolism in stable CF patients may be a result of chronic inflammation. PSA infection did not play a major role regarding these differences. Exacerbation increased and antibiotic therapy decreased sputum Arg concentrations. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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13 pages, 468 KiB  
Article
Monocyte Chemoattractant Protein-1 Is an Independent Predictor of Coronary Artery Ectasia in Patients with Acute Coronary Syndrome
by Juan Antonio Franco-Peláez, Roberto Martín-Reyes, Ana María Pello-Lázaro, Álvaro Aceña, Óscar Lorenzo, José Luis Martín-Ventura, Luis Blanco-Colio, María Luisa González-Casaus, Ignacio Hernández-González, Rocío Carda, María Luisa Martín-Mariscal, Jesús Egido and José Tuñón
J. Clin. Med. 2020, 9(9), 3037; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9093037 - 21 Sep 2020
Cited by 7 | Viewed by 2018
Abstract
Our purpose was to assess a possible association of inflammatory, lipid and mineral metabolism biomarkers with coronary artery ectasia (CAE) and to determine a possible association of this with acute atherotrombotic events (AAT). We studied 270 patients who underwent coronary angiography during an [...] Read more.
Our purpose was to assess a possible association of inflammatory, lipid and mineral metabolism biomarkers with coronary artery ectasia (CAE) and to determine a possible association of this with acute atherotrombotic events (AAT). We studied 270 patients who underwent coronary angiography during an acute coronary syndrome 6 months before. Plasma levels of several biomarkers were assessed, and patients were followed during a median of 5.35 (3.88–6.65) years. Two interventional cardiologists reviewed the coronary angiograms, diagnosing CAE according to previously published criteria in 23 patients (8.5%). Multivariate binary logistic regression analysis was used to search for independent predictors of CAE. Multivariate analysis revealed that, aside from gender and a diagnosis of dyslipidemia, only monocyte chemoattractant protein-1 (MCP-1) (OR = 2.25, 95%CI = (1.35–3.76) for each increase of 100 pg/mL, p = 0.001) was independent predictor of CAE, whereas mineral metabolism markers or proprotein convertase subtilisin/kexin type 9 were not. Moreover, CAE was a strong predictor of AAT during follow-up after adjustment for other clinically relevant variables (HR = 2.67, 95%CI = (1.22–5.82), p = 0.013). This is the first report showing that MCP-1 is an independent predictor of CAE, suggesting that CAE and coronary artery disease may share pathogenic mechanisms. Furthermore, CAE was associated with an increased incidence of AAT. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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12 pages, 2246 KiB  
Article
NGAL Correlates with Femoral and Carotid Plaque Volume Assessed by Sonographic 3D Plaque Volumetry
by Michael Schreinlechner, Maria Noflatscher, Daniela Lener, Axel Bauer, Rudolf Kirchmair, Peter Marschang and Markus Theurl
J. Clin. Med. 2020, 9(9), 2811; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9092811 - 31 Aug 2020
Cited by 6 | Viewed by 1550
Abstract
Background/Objectives: Inflammation represents a cornerstone in the development of atherosclerosis and early detection is essential to avoid cardiovascular events. Biomarkers like interleukin-1 beta, interleukin-6, or high sensitivity CRP (hs-CRP) have been investigated intensively in this field. Since they have several limitations, additional biomarkers [...] Read more.
Background/Objectives: Inflammation represents a cornerstone in the development of atherosclerosis and early detection is essential to avoid cardiovascular events. Biomarkers like interleukin-1 beta, interleukin-6, or high sensitivity CRP (hs-CRP) have been investigated intensively in this field. Since they have several limitations, additional biomarkers are needed for cardiovascular risk stratification. The acute phase protein, neutrophil gelatinase-associated lipocalin (NGAL), modulates inflammation and is elevated in cardiovascular disease (CVD). Moreover, it contributes to plaque destabilization. Methods: In this prospective, single-center study, we included 323 asymptomatic patients with at least one cardiovascular risk factor or established CVD. NGAL levels were measured in plasma samples using a commercially available ELISA. Carotid, femoral, and total atherosclerotic plaque volumes (PV) were measured using a 3D ultrasound system (Philips iU22). Patients were separated into a low (n = 243) and high (n = 80) total PV group. Results: NGAL was significantly higher in patients with high total PV versus patients with low total PV. The NGAL amplitude for the prediction of high total PV was significantly higher when compared with hs-CRP. A high predictive value could also be observed for patients without established CVD. Conclusion: NGAL seems to be a promising biomarker for the identification of asymptomatic patients with atherosclerotic disease. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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15 pages, 1814 KiB  
Article
Impact of Short-Term Hypoxia on Sirtuins as Regulatory Elements in HUVECs
by Simone Johanna Pecher, Arne Björn Potthast, Frauke von Versen-Höynck and Anibh Martin Das
J. Clin. Med. 2020, 9(8), 2604; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9082604 - 11 Aug 2020
Cited by 12 | Viewed by 2290
Abstract
Background: Sirtuins (SIRT) are NAD+-dependent deacetylases that are involved in stress response, antioxidative defense, and longevity via posttranslational modifications. SIRT1 directly activates nitric oxide synthase (NOS). Aging is associated with a reduced sirtuin function and reduction of the cofactor NAD+ [...] Read more.
Background: Sirtuins (SIRT) are NAD+-dependent deacetylases that are involved in stress response, antioxidative defense, and longevity via posttranslational modifications. SIRT1 directly activates nitric oxide synthase (NOS). Aging is associated with a reduced sirtuin function and reduction of the cofactor NAD+. Age-related atherosclerosis and vascular diseases are linked to a compromised sirtuin function. Vascular events like stroke and cardiac infarction result in acute hypoxia, which can additionally impact sirtuins and thus the vascular function. This prompted us to study sirtuins in intact HUVECs, under acute, short-term hypoxic conditions. Methods: We measured intracellular sirtuin and NAD+ levels in HUVECs exposed to hypoxia (2% O₂) for 10–120 min, compared to normoxic controls. SIRT1, SIRT3, and SIRT4 were measured at the protein (Western Blot) and the transcript level (qRT-PCR), SIRT1 and SIRT3 at the enzyme level (fluorometrically), and NAD+ levels were measured spectrophotometrically. Results: We observed a reduction of SIRT1 and SIRT4 at the protein level, a downregulation of SIRT1 at the transcript level and increased NAD+ levels under hypoxia. SIRT3 was not affected by hypoxia. Conclusions: Downregulation of SIRT1 under hypoxia might reduce production of the reactive oxygen species (ROS) via the respiratory chain and inhibit the mitochondrial ATP-synthase, resulting in energy conservation. NOS might be impaired if SIRT1 is decreased. Increased NAD+ levels might compensate these effects. Hypoxic downregulation of SIRT4 might lead to mitochondrial uncoupling, hence endothelial dysfunction, and ADP/ATP-translocase 2 (ANT2)-inhibition. NAD+ upregulation might partly compensate this effect. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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9 pages, 737 KiB  
Article
Association of Lower Plasma Homoarginine Concentrations with Greater Risk of All-Cause Mortality in the Community: The Framingham Offspring Study
by Edzard Schwedhelm, Rebecca J. Song, Ramachandran S. Vasan, Edwin R. van den Heuvel, Juliane Hannemann, Vanessa Xanthakis and Rainer Böger
J. Clin. Med. 2020, 9(6), 2016; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9062016 - 26 Jun 2020
Cited by 11 | Viewed by 2108
Abstract
Lower circulating homoarginine concentrations have been associated with morbidity and mortality in patients with established cardiovascular disease (CVD). We assayed plasma homoarginine concentrations in 3331 Framingham Offspring Study participants attending examination cycle six (mean age 58.6 years, 53% women). We evaluated correlates of [...] Read more.
Lower circulating homoarginine concentrations have been associated with morbidity and mortality in patients with established cardiovascular disease (CVD). We assayed plasma homoarginine concentrations in 3331 Framingham Offspring Study participants attending examination cycle six (mean age 58.6 years, 53% women). We evaluated correlates of plasma homoarginine and related homoarginine to incident CVD and death. We also classified participants as having higher (upper quartile) versus lower (lower three quartiles) homoarginine and previously assayed asymmetric dimethylarginine (ADMA) concentrations, and created cross-classification groups. We observed 630 incident CVD events and 940 deaths during a median follow-up of 18 years. In multivariable regression analysis, homoarginine was associated positively with male sex, body mass index, anti-hypertensive medication use and systolic blood pressure, but inversely with age and smoking. Higher homoarginine levels were associated with a lower mortality risk (hazard ratio (HR) per SD increment, 0.83, 95% CI: 0.74–0.93) adjusting for standard CVD risk factors, and ADMA. Among the cross-classification groups, participants with higher homoarginine and lower ADMA had a lower mortality risk (HR, 0.81, 95% CI: 0.67–0.98) compared to those with low levels of both. Further studies are needed to dissect the mechanisms of the association of homoarginine and mortality over decades in the community. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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21 pages, 547 KiB  
Article
Activated L-Arginine/Nitric Oxide Pathway in Pediatric Cystic Fibrosis and Its Association with Pancreatic Insufficiency, Liver Involvement and Nourishment: An Overview and New Results
by Folke Brinkmann, Beatrice Hanusch, Manfred Ballmann, Sebene Mayorandan, Alexander Bollenbach, Kristine Chobanyan-Jürgens, Kathrin Jansen, Anjona Schmidt-Choudhury, Nico Derichs, Dimitrios Tsikas and Thomas Lücke
J. Clin. Med. 2020, 9(6), 2012; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9062012 - 26 Jun 2020
Cited by 8 | Viewed by 3786
Abstract
Cystic fibrosis (CF; OMIM 219700) is a rare genetic disorder caused by a chloride channel defect, resulting in lung disease, pancreas insufficiency and liver impairment. Altered L-arginine (Arg)/nitric oxide (NO) metabolism has been observed in CF patients’ lungs and in connection with malnutrition. [...] Read more.
Cystic fibrosis (CF; OMIM 219700) is a rare genetic disorder caused by a chloride channel defect, resulting in lung disease, pancreas insufficiency and liver impairment. Altered L-arginine (Arg)/nitric oxide (NO) metabolism has been observed in CF patients’ lungs and in connection with malnutrition. The aim of the present study was to investigate markers of the Arg/NO pathway in the plasma and urine of CF patients and to identify possible risk factors, especially associated with malnutrition. We measured the major NO metabolites nitrite and nitrate, Arg, a semi-essential amino acid and NO precursor, the NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and its major urinary metabolite dimethylamine (DMA) in plasma and urine samples of 70 pediatric CF patients and 78 age-matched healthy controls. Biomarkers were determined by gas chromatography–mass spectrometry and high-performance liquid chromatography. We observed higher plasma Arg (90.3 vs. 75.6 µM, p < 0.0001), ADMA (0.62 vs. 0.57 µM, p = 0.03), Arg/ADMA ratio (148 vs. 135, p = 0.01), nitrite (2.07 vs. 1.95 µM, p = 0.03) and nitrate (43.3 vs. 33.1 µM, p < 0.001) concentrations, as well as higher urinary DMA (57.9 vs. 40.7 µM/mM creatinine, p < 0.001) and nitrate (159 vs. 115 µM/mM creatinine, p = 0.001) excretion rates in the CF patients compared to healthy controls. CF patients with pancreatic sufficiency showed plasma concentrations of the biomarkers comparable to those of healthy controls. Malnourished CF patients had lower Arg/ADMA ratios (p = 0.02), indicating a higher NO synthesis capacity in sufficiently nourished CF patients. We conclude that NO production, protein-arginine dimethylation, and ADMA metabolism is increased in pediatric CF patients. Pancreas and liver function influence Arg/NO metabolism. Good nutritional status is associated with higher NO synthesis capacity and lower protein-arginine dimethylation. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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13 pages, 6998 KiB  
Article
Impact of the Gut Microbiota on Atorvastatin Mediated Effects on Blood Lipids
by Friederike Zimmermann, Johann Roessler, David Schmidt, Andrzej Jasina, Paul Schumann, Martina Gast, Wolfgang Poller, David Leistner, Hector Giral, Nicolle Kränkel, Adelheid Kratzer, Sven Schuchardt, Markus M. Heimesaat, Ulf Landmesser and Arash Haghikia
J. Clin. Med. 2020, 9(5), 1596; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9051596 - 25 May 2020
Cited by 14 | Viewed by 4105
Abstract
Background and Aims: The mechanisms of interindividual variation of lipid regulation by statins, such as the low-density lipoprotein cholesterol (LDL) lowering effects, are not fully understood yet. Here, we used a gut microbiota depleted mouse model to investigate the relation between the gut [...] Read more.
Background and Aims: The mechanisms of interindividual variation of lipid regulation by statins, such as the low-density lipoprotein cholesterol (LDL) lowering effects, are not fully understood yet. Here, we used a gut microbiota depleted mouse model to investigate the relation between the gut microbiota and the regulatory property of atorvastatin on blood lipids. Methods: Mice (C57BL/6) with intact gut microbiota or antibiotic induced abiotic mice (ABS) were put on standard chow diet (SCD) or high fat diet (HFD) for six weeks. Atorvastatin (10 mg/kg body weight/day) or a control vehicle were applied per gavage for the last four weeks of dietary treatment. Blood lipids including total cholesterol, very low-density lipoprotein, low-density lipoprotein, high-density lipoprotein and sphingolipids were measured to probe microbiota-dependent effects of atorvastatin. The expression of genes involved in hepatic and intestinal cholesterol metabolism was analyzed with qRT-PCR. The alteration of the microbiota profile was examined using 16S rRNA qPCR in mice with intact gut microbiota. Results: HFD feeding significantly increased total blood cholesterol and LDL levels, as compared to SCD in both mice with intact and depleted gut microbiota. The cholesterol lowering effect of atorvastatin was significantly attenuated in mice with depleted gut microbiota. Moreover, we observed a global shift in the abundance of several sphingolipids upon atorvastatin treatment which was absent in gut microbiota depleted mice. The regulatory effect of atorvastatin on the expression of distinct hepatic and intestinal cholesterol-regulating genes, including Ldlr, Srebp2 and Npc1l1 was altered upon depletion of gut microbiota. In response to HFD feeding, the relative abundance of the bacterial phyla Bacteroidetes decreased, while the abundance of Firmicutes increased. The altered ratio between Firmicutes to Bacteroidetes was partly reversed in HFD fed mice treated with atorvastatin. Conclusions: Our findings support a regulatory impact of atorvastatin on the gut microbial profile and, in turn, demonstrate a crucial role of the gut microbiome for atorvastatin-related effects on blood lipids. These results provide novel insights into potential microbiota-dependent mechanisms of lipid regulation by statins, which may account for variable response to statin treatment. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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17 pages, 1387 KiB  
Article
Selected Atherosclerosis-Related Diseases May Differentially Affect the Relationship between Plasma Advanced Glycation End Products, Receptor sRAGE, and Uric Acid
by Bogna Gryszczyńska, Magdalena Budzyń, Dorota Formanowicz, Maria Wanic-Kossowska, Piotr Formanowicz, Wacław Majewski, Maria Iskra and Magdalena P. Kasprzak
J. Clin. Med. 2020, 9(5), 1416; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9051416 - 10 May 2020
Cited by 6 | Viewed by 2282
Abstract
Our study aimed to identify the relationship between advanced glycation end products (AGEs), soluble receptor for advanced glycation end products (sRAGE), the AGEs/sRAGE, and uric acid (UA) levels in selected atherosclerosis diseases, i.e., abdominal aortic aneurysms (AAA), aortoiliac occlusive disease (AIOD), and chronic [...] Read more.
Our study aimed to identify the relationship between advanced glycation end products (AGEs), soluble receptor for advanced glycation end products (sRAGE), the AGEs/sRAGE, and uric acid (UA) levels in selected atherosclerosis diseases, i.e., abdominal aortic aneurysms (AAA), aortoiliac occlusive disease (AIOD), and chronic kidney disease (CKD), resulting from apparent differences in oxidative stress intensity. Furthermore, we suggest that increased AGEs levels may stimulate an antioxidant defense system reflected by the UA level. The studied group size consisted of 70 AAA patients, 20 AIOD patients, 50 patients in the pre-dialyzed group (PRE), and 35 patients in the hemodialyzed group (HD). The enzyme-linked immunosorbent assay was used to measure AGEs and sRAGE levels. We found a significantly higher concentration of AGEs in CKD patients as compared to AAA and AIOD patients. Furthermore, the sRAGE level was higher in the CKD patients in comparison to AIOD and AAA patients. UA level was significantly higher in the PRE group compared to AAA patients. In conclusion, the diseases included in this study differ in the anti- and prooxidant defense system, which is reflected in the relations between the AGEs, the sRAGE, the AGEs/sRAGE ratio, as well as the UA levels. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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16 pages, 1973 KiB  
Article
Pre-Analytical and Clinical Validation of a Dried Blood Spot Assay for Asymmetric Dimethylarginine and L-Arginine
by Juliane Hannemann, Thore I. Roskam, Ina Eilermann, Patricia Siques, Julio Brito and Rainer Böger
J. Clin. Med. 2020, 9(4), 1072; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9041072 - 09 Apr 2020
Cited by 4 | Viewed by 2248
Abstract
Asymmetric dimethylarginine (ADMA) inhibits nitric oxide (NO) synthesis. It is a risk marker for cardiovascular events and mortality in patients with cardiometabolic diseases and in population-based studies. Plasma or serum analysis of ADMA may be hampered by pre-analytical sample handling. We validated a [...] Read more.
Asymmetric dimethylarginine (ADMA) inhibits nitric oxide (NO) synthesis. It is a risk marker for cardiovascular events and mortality in patients with cardiometabolic diseases and in population-based studies. Plasma or serum analysis of ADMA may be hampered by pre-analytical sample handling. We validated a dried blood spot (DBS) assay for ADMA and L-arginine and show here that this assay has excellent variabilities and reproducibilities. Filter paper is impregnated with the arginase inhibitor nor-NOHA (Nω-hydroxy-nor-Arginine) to avoid L-arginine degradation. Clinical validation of this DBS assay confirms elevated ADMA concentration in hemodialysis patients as compared to healthy controls, higher ADMA concentrations in men versus women, and elevated L-arginine concentration in subjects supplemented with L-arginine. The DBS assay was used in a cohort study involving 100 primarily healthy subjects in the Andean region to assess the impact of chronic intermittent hypoxia on ADMA and L-arginine; ADMA DBS concentration at sea level was prospectively associated with pulmonary hypertension after six months of exposure to 3500 m. In a cohort of 753 individuals, L-arginine/ADMA ratio significantly decreased with increasing number of traditional cardiovascular risk factors. Analysis of ADMA and L-arginine in DBS is a reliable and reproducible method for quantitation of these markers in field studies. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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11 pages, 1664 KiB  
Article
Subclinical Arteriosclerosis is Associated with Common Vascular Risk Factors in Long-Term Survivors of Testicular Cancer
by Javier Espíldora-Hernández, Tania Díaz-Antonio, Javier Baena-Espinar, Inmaculada Alonso-Calderón, José Rioja, Emilio Alba-Conejo, Pedro Valdivielso and Miguel-Ángel Sánchez-Chaparro
J. Clin. Med. 2020, 9(4), 971; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9040971 - 31 Mar 2020
Viewed by 2122
Abstract
Cardiovascular disease risk is increased in survivors of testicular cancer because of exposure to treatment (chemotherapy and radiotherapy), as well as modification in lifestyle. Our aim was to assess the presence of subclinical arteriosclerosis in survivors of testicular cancer in comparison with a [...] Read more.
Cardiovascular disease risk is increased in survivors of testicular cancer because of exposure to treatment (chemotherapy and radiotherapy), as well as modification in lifestyle. Our aim was to assess the presence of subclinical arteriosclerosis in survivors of testicular cancer in comparison with a control group. This was a cross-sectional, observational, case–control study including 50 survivors of Germ Cell Tumor (GCT) (14 years of follow-up) and 53 age-matched controls with no cancer. We registered clinical data, cardiovascular risk factors, physical and Mediterranean questionnaires, intima-media thickness and plaque at carotid and femoral arteries by ultrasound, calcium score at the abdominal aorta, and liver steatosis by computed tomography, and applied analytical tests to quantify metabolic risk factors and inflammation markers. Patients showed a trend toward greater intima-media thickness (IMT) and plaques than controls, as well as a higher calcium score in the abdominal aorta. Remarkably, patients had higher waist circumference, insulin resistance (HOMA-IR), and liver steatosis, but lower physical activity and high-density lipoprotein (HDL) cholesterol than controls (all p < 0.05). In multivariate analyses, only common vascular risk factors were associated with subclinical arteriosclerosis. As a conclusion, in our study, a higher rate of subclinical arteriosclerosis in testicular cancer survivors was associated with classical metabolic risk factors and lifestyle, but not with exposure to chemotherapy. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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Graphical abstract

16 pages, 315 KiB  
Article
An Ethnic Comparison of Arginine Dimethylation and Cardiometabolic Factors in Healthy Black and White Youth: The ASOS and African-PREDICT Studies
by Alexander Bollenbach, Aletta E. Schutte, Ruan Kruger and Dimitrios Tsikas
J. Clin. Med. 2020, 9(3), 844; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9030844 - 20 Mar 2020
Cited by 12 | Viewed by 2158
Abstract
Proteinic arginine dimethylation (PADiMe) is a major post-translational modification. Proteolysis of asymmetric and symmetric PADiMe products releases asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), respectively, two endogenous atherogenic substances. SDMA, ADMA, and its major metabolite dimethylamine (DMA) are eliminated by the kidney. The [...] Read more.
Proteinic arginine dimethylation (PADiMe) is a major post-translational modification. Proteolysis of asymmetric and symmetric PADiMe products releases asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), respectively, two endogenous atherogenic substances. SDMA, ADMA, and its major metabolite dimethylamine (DMA) are eliminated by the kidney. The urinary concentrations of DMA+ADMA, SDMA, and DMA+ADMA+SDMA are useful measures of the whole-body asymmetric and symmetric PADiMe, respectively. Urinary (DMA+ADMA)/SDMA is an index of the asymmetric to symmetric PADiMe balance. In two bi-ethnic studies, the ASOS (39 black boys, 41 white boys) and the African-PREDICT (292 black young men, 281 white young men) studies, we investigated whether ethnicity is a major determinant of PADiMe, and whether PADiMe is associated with blood pressure and ethnicity-dependent growth and inflammatory factors, including HDL. DMA, ADMA, and SDMA were measured in spot urine samples by gas chromatography–mass spectrometry, and their excretion was corrected for creatinine excretion. In black boys, creatinine-corrected DMA, DMA+ADMA, and DMA+ADMA+SDMA concentrations were lower by 11.7%, 9.5%, and 7.6% (all p < 0.05), respectively, compared to the white boys, and 3.4%, 2.0%, and 1.8% lower (all p < 0.05), respectively, in black compared to white men. (DMA+ADMA)/SDMA did not differ between black boys and black men, but was higher in white boys compared to white men. ADMA did not differ between black and white boys, or between black and white men. Creatinine-corrected SDMA excretion was lower in black boys compared to white boys (by 8%) and to white men (by 3.1%). None of the PADiMe indices were associated with blood pressure in either study. IGF-binding protein 3 correlated inversely with all PADiMe indices in the black men only. Our study showed that asymmetric proteinic arginine dimethylation is higher in white boys than in black boys, and that this difference disappears in adulthood. ADMA metabolism and SDMA excretion were lower in the black subjects compared to the white subjects, suggesting ethnicity-dependent hepatic and renal elimination of ADMA and SDMA in the childhood. The results of our study may have clinical relevance beyond atherosclerosis, such as in growth and inflammation, which have not been sufficiently addressed thus far. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
14 pages, 940 KiB  
Article
Enhanced Nitric Oxide (NO) and Decreased ADMA Synthesis in Pediatric ADHD and Selective Potentiation of NO Synthesis by Methylphenidate
by Kathrin Jansen, Beatrice Hanusch, Saskia Pross, Erik Hanff, Kathrin Drabert, Alexander Bollenbach, Irina Dugave, Christina Carmann, Rainer Georg Siefen, Barbara Emons, Georg Juckel, Tanja Legenbauer, Dimitrios Tsikas and Thomas Lücke
J. Clin. Med. 2020, 9(1), 175; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9010175 - 08 Jan 2020
Cited by 7 | Viewed by 3551
Abstract
Attention deficit hyperactivity disorder (ADHD) is a common pediatric psychiatric disorder, frequently treated with methylphenidate (MPH). Recently, MPH’s cardiovascular safety has been questioned by observational studies describing an increased cardiovascular risk in adults and blood pressure alterations in children. We considered members of [...] Read more.
Attention deficit hyperactivity disorder (ADHD) is a common pediatric psychiatric disorder, frequently treated with methylphenidate (MPH). Recently, MPH’s cardiovascular safety has been questioned by observational studies describing an increased cardiovascular risk in adults and blood pressure alterations in children. We considered members of the L-arginine (Arg)/nitric oxide (NO) pathway as possible early cardiovascular risk factors in pediatric ADHD children. They include the NO metabolites, nitrite and nitrate, the NO precursor Arg, and asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor and a cardiovascular risk factor in adults. We conducted a prospective clinical trial with 42 ADHD children (aged 6–16 years) with (n = 19) and without (n = 23) MPH treatment. Age-matched children without ADHD (n = 43) served as controls. All plasma and urine metabolites were determined by gas chromatography-mass spectrometry. We observed higher plasma nitrite and lower plasma ADMA concentrations in the ADHD children. MPH-treated ADHD children had higher plasma nitrite concentrations than MPH-untreated ADHD children. As NOS activity is basally inhibited by ADMA, MPH treatment seems to have decreased the inhibitory potency of ADMA. Percentiles of systolic blood pressure were higher in MPH-treated ADHD children. The underlying mechanisms and their implications in the MPH therapy of pediatric ADHD with MPH remain to be elucidated in larger cohorts. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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Review

Jump to: Research

41 pages, 6574 KiB  
Review
Transport of L-Arginine Related Cardiovascular Risk Markers
by Sofna Banjarnahor, Roman N. Rodionov, Jörg König and Renke Maas
J. Clin. Med. 2020, 9(12), 3975; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9123975 - 08 Dec 2020
Cited by 21 | Viewed by 4062
Abstract
L-arginine and its derivatives, asymmetric and symmetric dimethylarginine (ADMA and SDMA) and L-homoarginine, have emerged as cardiovascular biomarkers linked to cardiovascular outcomes and various metabolic and functional pathways such as NO-mediated endothelial function. Cellular uptake and efflux of L-arginine and its derivatives are [...] Read more.
L-arginine and its derivatives, asymmetric and symmetric dimethylarginine (ADMA and SDMA) and L-homoarginine, have emerged as cardiovascular biomarkers linked to cardiovascular outcomes and various metabolic and functional pathways such as NO-mediated endothelial function. Cellular uptake and efflux of L-arginine and its derivatives are facilitated by transport proteins. In this respect the cationic amino acid transporters CAT1 and CAT2 (SLC7A1 and SLC7A2) and the system y+L amino acid transporters (SLC7A6 and SLC7A7) have been most extensively investigated, so far, but the number of transporters shown to mediate the transport of L-arginine and its derivatives is constantly increasing. In the present review we assess the growing body of evidence regarding the function, expression, and clinical relevance of these transporters and their possible relation to cardiovascular diseases. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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15 pages, 256 KiB  
Review
Role of the Fatty Acid Binding Proteins in Cardiovascular Diseases: A Systematic Review
by Hien C. Nguyen, Mohammad Qadura and Krishna K. Singh
J. Clin. Med. 2020, 9(11), 3390; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9113390 - 22 Oct 2020
Cited by 22 | Viewed by 2616
Abstract
Cardiovascular diseases (CVD) remain a global pandemic and leading cause of deaths worldwide. While several guidelines have been developed to control the development of CVDs, its prevalence keeps on increasing until this day. Cardiovascular risk factors, such as reduced exercises and high fat [...] Read more.
Cardiovascular diseases (CVD) remain a global pandemic and leading cause of deaths worldwide. While several guidelines have been developed to control the development of CVDs, its prevalence keeps on increasing until this day. Cardiovascular risk factors, such as reduced exercises and high fat or glucose diets, culminate in the development of the metabolic syndrome and eventually atherosclerosis, which is driven by high blood lipid and cholesterol levels, and by endothelial dysfunction. Late complications of atherosclerosis give rise to serious clinical cardiovascular manifestations such as myocardial infarction and hypertension. Therefore, endothelial functions and the lipid metabolism play critical roles in the pathogenesis of CVDs. Fatty acid-binding proteins are a family of intracellular proteins expressed in many cell types known mainly for their interaction with and trafficking of cellular lipids. The roles of a number of isoforms in this family have been implicated in lipid metabolic homeostasis, but their influence on endothelial function and vascular homeostasis remain largely unknown. This review’s purpose is to update fundamentals about the connection between cardiovascular disease, metabolism, endothelial function, and mainly the roles of fatty acid-binding proteins. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
17 pages, 968 KiB  
Review
ADMA: A Key Player in the Relationship between Vascular Dysfunction and Inflammation in Atherosclerosis
by Laura Dowsett, Erin Higgins, Sarah Alanazi, Noha A. Alshuwayer, Fiona C. Leiper and James Leiper
J. Clin. Med. 2020, 9(9), 3026; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9093026 - 20 Sep 2020
Cited by 47 | Viewed by 4037
Abstract
Atherosclerosis is a chronic cardiovascular disease which increases risk of major cardiovascular events including myocardial infarction and stroke. Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) have long been recognised as a hallmark of cardiovascular disease and are associated with cardiovascular risk factors including [...] Read more.
Atherosclerosis is a chronic cardiovascular disease which increases risk of major cardiovascular events including myocardial infarction and stroke. Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) have long been recognised as a hallmark of cardiovascular disease and are associated with cardiovascular risk factors including hypertension, obesity and hypertriglyceridemia. In this review, we discuss the clinical literature that link ADMA concentrations to increased risk of the development of atherosclerosis. The formation of atherosclerotic lesions relies on the interplay between vascular dysfunction, leading to endothelial activation and the accumulation of inflammatory cells, particularly macrophages, within the vessel wall. Here, we review the mechanisms through which elevated ADMA contributes to endothelial dysfunction, activation and reactive oxygen species (ROS) production; how ADMA may affect vascular smooth muscle phenotype; and finally whether ADMA plays a regulatory role in the inflammatory processes occurring within the vessel wall. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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13 pages, 477 KiB  
Review
The Use of Vasoactive Drugs in the Treatment of Male Erectile Dysfunction: Current Concepts
by George T. Kedia, Stefan Ückert, Dimitrios Tsikas, Armin J. Becker, Markus A. Kuczyk and Andreas Bannowsky
J. Clin. Med. 2020, 9(9), 2987; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9092987 - 16 Sep 2020
Cited by 10 | Viewed by 3343
Abstract
It is widely accepted that disorders of the male (uro)genital tract, such as erectile dysfunction (ED) and benign diseases of the prostate (lower urinary tract symptomatology or benign prostatic hyperplasia), can be approached therapeutically by influencing the function of both the vascular and [...] Read more.
It is widely accepted that disorders of the male (uro)genital tract, such as erectile dysfunction (ED) and benign diseases of the prostate (lower urinary tract symptomatology or benign prostatic hyperplasia), can be approached therapeutically by influencing the function of both the vascular and non-vascular smooth muscle of the penile erectile tissue or the transition zone/periurethral region of the prostate, respectively. As a result of the discovery of nitric oxide (NO) and cyclic guanosine monophosphate (GMP) as central mediators of penile smooth muscle relaxation, the use of drugs known to increase the local production of NO and/or elevate the intracellular level of the second messenger cyclic GMP have attracted broad attention in the treatment of ED of various etiologies. Specifically, the introduction of vasoactive drugs, including orally active inhibitors of the cyclic GMP-specific phosphodiesterase (PDE) 5, has offered great advantage in the pharmacotherapy of ED and other diseases of the genitourinary tract. These drugs have been proven efficacious with a fast on-set of action and an improved profile of side-effects. This review summarizes current strategies for the treatment of ED utilizing the application of vasoactive drugs via the oral, transurethral, topical, or self-injection route. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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27 pages, 1010 KiB  
Review
Endothelial Dysfunction in Chronic Kidney Disease, from Biology to Clinical Outcomes: A 2020 Update
by Stefanos Roumeliotis, Francesca Mallamaci and Carmine Zoccali
J. Clin. Med. 2020, 9(8), 2359; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9082359 - 23 Jul 2020
Cited by 119 | Viewed by 7010
Abstract
The vascular endothelium is a dynamic, functionally complex organ, modulating multiple biological processes, including vascular tone and permeability, inflammatory responses, thrombosis, and angiogenesis. Endothelial dysfunction is a threat to the integrity of the vascular system, and it is pivotal in the pathogenesis of [...] Read more.
The vascular endothelium is a dynamic, functionally complex organ, modulating multiple biological processes, including vascular tone and permeability, inflammatory responses, thrombosis, and angiogenesis. Endothelial dysfunction is a threat to the integrity of the vascular system, and it is pivotal in the pathogenesis of atherosclerosis and cardiovascular disease. Reduced nitric oxide (NO) bioavailability is a hallmark of chronic kidney disease (CKD), with this disturbance being almost universal in patients who reach the most advanced phase of CKD, end-stage kidney disease (ESKD). Low NO bioavailability in CKD depends on several mechanisms affecting the expression and the activity of endothelial NO synthase (eNOS). Accumulation of endogenous inhibitors of eNOS, inflammation and oxidative stress, advanced glycosylation products (AGEs), bone mineral balance disorders encompassing hyperphosphatemia, high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23), and low levels of the active form of vitamin D (1,25 vitamin D) and the anti-ageing vasculoprotective factor Klotho all impinge upon NO bioavailability and are critical to endothelial dysfunction in CKD. Wide-ranging multivariate interventions are needed to counter endothelial dysfunction in CKD, an alteration triggering arterial disease and cardiovascular complications in this high-risk population. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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15 pages, 346 KiB  
Review
Endothelial Dysfunction: A Contributor to Adverse Cardiovascular Remodeling and Heart Failure Development in Type 2 Diabetes beyond Accelerated Atherogenesis
by Aleksandra Gamrat, Michał A. Surdacki, Bernadeta Chyrchel and Andrzej Surdacki
J. Clin. Med. 2020, 9(7), 2090; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9072090 - 03 Jul 2020
Cited by 19 | Viewed by 2893
Abstract
Endothelial dysfunction, associated with depressed nitric oxide (NO) bioavailability, is a well-recognized contributor to both accelerated atherogenesis and microvascular complications in type 2 diabetes (DM). However, growing evidence points to the comorbidities-driven endothelial dysfunction within coronary microvessels as a key player responsible for [...] Read more.
Endothelial dysfunction, associated with depressed nitric oxide (NO) bioavailability, is a well-recognized contributor to both accelerated atherogenesis and microvascular complications in type 2 diabetes (DM). However, growing evidence points to the comorbidities-driven endothelial dysfunction within coronary microvessels as a key player responsible for left ventricular (LV) diastolic dysfunction, restrictive LV remodeling and heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure in DM. In this review we have described: (1) multiple cellular pathways which may link depressed NO bioavailability to LV diastolic dysfunction and hypertrophy; (2) hemodynamic consequences and prognostic effects of restrictive LV remodeling and combined diastolic and mild systolic LV dysfunction on cardiovascular outcomes in DM and HFpEF, with a focus on the clinical relevance of endothelial dysfunction; (3) novel therapeutic strategies to improve endothelial function in DM. In summary, beyond associations with accelerated atherogenesis and microvascular complications, endothelial dysfunction supplements the multiple interwoven pathways affecting cardiomyocytes, endothelial cells and the extracellular matrix with consequent LV dysfunction in DM patients. The association amongst impaired endothelial function, reduced coronary flow reserve, combined LV diastolic and discrete systolic dysfunction, and low LV stroke volume and preload reserve—all of which are adverse outcome predictors—is a dangerous constellation of inter-related abnormalities, underlying the development of heart failure. Nevertheless, the relevance of endothelial effects of novel drugs in terms of their ability to attenuate cardiovascular remodeling and delay heart failure onset in DM patients remains to be investigated. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
19 pages, 2491 KiB  
Review
Urinary Dimethylamine (DMA) and Its Precursor Asymmetric Dimethylarginine (ADMA) in Clinical Medicine, in the Context of Nitric Oxide (NO) and Beyond
by Dimitrios Tsikas
J. Clin. Med. 2020, 9(6), 1843; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9061843 - 12 Jun 2020
Cited by 26 | Viewed by 3644
Abstract
Asymmetric protein-arginine dimethylation is a major post-translational modification (PTM) catalyzed by protein-arginine methyltransferase (PRMT). Regular proteolysis releases asymmetric dimethylarginine (ADMA). Of the daily produced ADMA, about 10% are excreted unchanged in the urine. The remaining 90% are hydrolyzed by dimethylarginine dimethylaminohydrolase (DDAH) to [...] Read more.
Asymmetric protein-arginine dimethylation is a major post-translational modification (PTM) catalyzed by protein-arginine methyltransferase (PRMT). Regular proteolysis releases asymmetric dimethylarginine (ADMA). Of the daily produced ADMA, about 10% are excreted unchanged in the urine. The remaining 90% are hydrolyzed by dimethylarginine dimethylaminohydrolase (DDAH) to L-citrulline and dimethylamine (DMA), which is readily excreted in the urine. The PRMT/DDAH pathway is almost the exclusive origin of urinary ADMA and the major source of urinary DMA. Dietary fish and seafood represent additional abundant sources of urinary DMA. The present article provides an overview of urinary ADMA and DMA reported thus far in epidemiological, clinical and pharmacological studies, in connection with the L-arginine/nitric oxide (NO) pathway and beyond, in neonates, children and adolescents, young and elderly subjects, males and females. Discussed diseases mainly include those relating to the renal and cardiovascular systems such as peripheral arterial occlusive disease, coronary artery disease, chronic kidney disease, rheumatoid arthritis, Becker muscular disease, Duchenne muscular disease (DMD), attention deficit hyperactivity disorder (ADHD), and type I diabetes. Under standardized conditions involving the abstinence of DMA-rich fresh and canned fish and seafood, urinary DMA and ADMA are useful as measures of whole-body asymmetric arginine-dimethylation in health and disease. The creatinine-corrected excretion rates of DMA range from 10 to 80 µmol/mmol in adults and up to 400 µmol/mmol in children and adolescents. The creatinine-corrected excretion rates of ADMA are on average 10 times lower. In general, diseases are associated with higher urinary DMA and ADMA excretion rates, and pharmacological treatment, such as with steroids and creatine (in DMD), decreases their excretion rates, which may be accompanied by a decreased urinary excretion of nitrate, the major metabolite of NO. In healthy subjects and in rheumatoid arthritis patients, the urinary excretion rate of DMA correlates positively with the excretion rate of dihydroxyphenylglycol (DHPG), the major urinary catecholamines metabolite, suggesting a potential interplay in the PRMT/DDAH/NO pathway. Full article
(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)
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