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Biomedicines
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Aging, Inflammaging and Multimorbidity: What Is the Role of Endothelial...
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Aging, Inflammaging and Multimorbidity: What Is the Role of Endothelial Dysfunction?

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 11445

Special Issue Editors

Dr. Giuseppina Basta

E-Mail Website
Guest Editor
Institute of Clinical Physiology, National Research Council (Cnr), via Moruzzi, 1, 56124 Pisa, Italy
Interests: inflammation; endothelial dysfunction; atherosclerosis; disease biomarkers
Special Issues, Collections and Topics in MDPI journals
Dr. Serena Del Turco

E-Mail Website
Guest Editor
Institute of Clinical Physiology, National Research Council (Cnr), via Moruzzi, 1, 56124 Pisa, Italy
Interests: oxidative stress; inflammation; vascular disease; cardiometabolic biomarkers and nanotechnology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Endothelial dysfunction or loss of physiological properties such as vascular tone control, vascular permeability, hemostasis, neutrophil recruitment, and hormonal traffic, is a systemic alteration resulting in the induction of a pro-coagulant, anti-fibrinolytic state and low-chronic inflammation (inflammaging). With aging, the endothelial environment is perturbed by an increase in cytokines, chemokines, growth factors, proteases, and angiogenic factors that characterize a senescence-associated proinflammatory secretory phenotype, which results in a high susceptibility to chronic morbidity, disability, frailty, and death.

A dysfunctional endothelium not only characterizes aging but accompanies chronic diseases, such as hypertension, dyslipidemia, diabetes mellitus, cardiovascular and cerebrovascular diseases, chronic pulmonary, renal, and liver diseases, which are associated with persistent and unresolved production of pro-inflammatory mediators also in young adults, increasing the risk of age-related morbidity and premature mortality. Inflammation driven by metabolic imbalance, called meta-inflammation, is another important cellular deregulatory manifestation, closely associated with a pro-inflammatory phenotype inducing premature aging and related chronic pathologies, particularly vascular diseases.

The pathophysiological mechanisms involved in the failure of endothelial function are multifactorial, including the reduction of nitric oxide bioavailability downstream of oxidative stress and inflammation, genomic instability, altered cell repair mechanisms, and loss of autophagy.

Given the negative effects of inflammaging on aging and associated comorbidities, given the central role of endothelium and the current inability to precisely control systemic inflammation, a careful monitoring and possible therapeutic intervention of endothelial dysfunction becomes a priority to avoid pathological and premature aging.

Dr. Giuseppina Basta
Dr. Serena Del Turco
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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • aging
  • inflammaging
  • vascular disease
  • frailty
  • oxidative stress
  • endothelial dysfunction
  • comorbidity
  • autophagy
  • cellular senescence

Published Papers (5 papers)

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Research

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11 pages, 1116 KiB  
Article
Mutual Effect Modification between Insulin Resistance and Endothelial Dysfunction in Predicting Incident Heart Failure in Hypertensives
by Maria Perticone, Raffaele Maio, Simona Gigliotti, Ermal Shehaj, Alfredo Francesco Toscani, Antonella Capomolla, Ginevra Fabiani, Angela Sciacqua and Francesco Perticone
Biomedicines 2023, 11(8), 2188; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11082188 - 03 Aug 2023
Cited by 2 | Viewed by 712
Abstract
Insulin resistance and endothelial dysfunction are associated with heart failure (HF). Our objective was to investigate whether endothelial dysfunction and insulin resistance are independent predictors of incident HF and if a possible interaction exists between them. We enrolled 705 white never-treated hypertensives. Endothelium-dependent [...] Read more.
Insulin resistance and endothelial dysfunction are associated with heart failure (HF). Our objective was to investigate whether endothelial dysfunction and insulin resistance are independent predictors of incident HF and if a possible interaction exists between them. We enrolled 705 white never-treated hypertensives. Endothelium-dependent vasodilation was investigated by intra-arterial infusion of acetylcholine. During the follow-up [median: 117 months (range: 31–211)], we documented 223 new cases of HF (3.3 events/100 patient-years). We stratified the study population into progressors and non-progressors; progressors showed an older age and a higher prevalence of females, as well as higher mean values of baseline glucose, insulin, homeostasis model assessment (HOMA), creatinine, and high-sensitivity C-reactive protein (hs-CRP), whereas the estimated glomerular filtration rate (e-GFR) and endothelium-dependent vasodilation were lower. In the multiple Cox regression analysis, serum hs-CRP (HR = 1.362, (95% CI = 1.208–1.536), HOMA (HR = 1.293, 95% CI = 1.142–1.465), maximal acetylcholine (Ach)-stimulated forearm blood flow (FBF) (100% increment, HR = 0.807, 95% CI = 0.697–0.934), and e-GFR (10 mL/min/1.73 m2 increment, HR = 0.552, 95% CI = 0.483–0.603) maintained an independent association with incident HF. HOMA and endothelial dysfunction interact between them in a competitive manner (HR = 6.548, 95% CI = 4.034–10.629), also showing a mutual effect modification. Our findings demonstrate that both endothelial dysfunction and HOMA are independent and strong predictors of incident HF in hypertensives, these two risk factors interact between them with a competitive mechanism. Full article
(This article belongs to the Special Issue Aging, Inflammaging and Multimorbidity: What Is the Role of Endothelial Dysfunction?)
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13 pages, 2855 KiB  
Article
Apolipoprotein C3-Rich Low-Density Lipoprotein Induces Endothelial Cell Senescence via FBXO31 and Its Inhibition by Sesamol In Vitro and In Vivo
by Ping-Hsuan Tsai, Li-Zhen Chen, Kuo-Feng Tseng, Fang-Yu Chen and Ming-Yi Shen
Biomedicines 2022, 10(4), 854; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040854 - 05 Apr 2022
Cited by 6 | Viewed by 1848
Abstract
Premature endothelial senescence decreases the atheroprotective capacity of the arterial endothelium. Apolipoprotein C3 (ApoC3) delays the catabolism of triglyceride-rich particles and plays a critical role in atherosclerosis progression. FBXO31 is required for the intracellular response to DNA damage, which is a significant cause [...] Read more.
Premature endothelial senescence decreases the atheroprotective capacity of the arterial endothelium. Apolipoprotein C3 (ApoC3) delays the catabolism of triglyceride-rich particles and plays a critical role in atherosclerosis progression. FBXO31 is required for the intracellular response to DNA damage, which is a significant cause of cellular senescence. Sesamol is a natural antioxidant with cardiovascular-protective properties. In this study, we aimed to examine the effects of ApoC3-rich low-density lipoprotein (AC3RL) mediated via FBXO31 on endothelial cell (EC) senescence and its inhibition by sesamol. AC3RL and ApoC3-free low-density lipoproteins (LDL) (AC3(-)L) were isolated from the plasma LDL of patients with ischemic stroke. Human aortic endothelial cells (HAECs) treated with AC3RL induced EC senescence in a dose-dependent manner. AC3RL induced HAEC senescence via DNA damage. However, silencing FBXO31 attenuated AC3RL-induced DNA damage and reduced cellular senescence. Thus, FBXO31 may be a novel therapeutic target for endothelial senescence-related cardiovascular diseases. Moreover, the aortic arch of hamsters fed a high-fat diet with sesamol showed a substantial reduction in their atherosclerotic lesion size. In addition to confirming the role of AC3RL in aging and atherosclerosis, we also identified AC3RL as a potential therapeutic target that can be used to combat atherosclerosis and the onset of cardiovascular disease in humans. Full article
(This article belongs to the Special Issue Aging, Inflammaging and Multimorbidity: What Is the Role of Endothelial Dysfunction?)
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11 pages, 887 KiB  
Article
Clinical Phenotype Classification of Atrial Fibrillation Patients Using Cluster Analysis and Associations with Trial-Adjudicated Outcomes
by Marco Vitolo, Marco Proietti, Alena Shantsila, Giuseppe Boriani and Gregory Y. H. Lip
Biomedicines 2021, 9(7), 843; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070843 - 20 Jul 2021
Cited by 17 | Viewed by 3215
Abstract
Background and purpose: Given the great clinical heterogeneity of atrial fibrillation (AF) patients, conventional classification only based on disease subtype or arrhythmia patterns may not adequately characterize this population. We aimed to identify different groups of AF patients who shared common clinical phenotypes [...] Read more.
Background and purpose: Given the great clinical heterogeneity of atrial fibrillation (AF) patients, conventional classification only based on disease subtype or arrhythmia patterns may not adequately characterize this population. We aimed to identify different groups of AF patients who shared common clinical phenotypes using cluster analysis and evaluate the association between identified clusters and clinical outcomes. Methods: We performed a hierarchical cluster analysis in AF patients from AMADEUS and BOREALIS trials. The primary outcome was a composite of stroke/thromboembolism (TE), cardiovascular (CV) death, myocardial infarction, and/or all-cause death. Individual components of the primary outcome and major bleeding were also assessed. Results: We included 3980 AF patients treated with the Vitamin-K Antagonist from the AMADEUS and BOREALIS studies. The analysis identified four clusters in which patients varied significantly among clinical characteristics. Cluster 1 was characterized by patients with low rates of CV risk factors and comorbidities; Cluster 2 was characterized by patients with a high burden of CV risk factors; Cluster 3 consisted of patients with a high burden of CV comorbidities; Cluster 4 was characterized by the highest rates of non-CV comorbidities. After a mean follow-up of 365 (standard deviation 187) days, Cluster 4 had the highest cumulative risk of outcomes. Compared with Cluster 1, Cluster 4 was independently associated with an increased risk for the composite outcome (hazard ratio (HR) 2.43, 95% confidence interval (CI) 1.70–3.46), all-cause death (HR 2.35, 95% CI 1.58–3.49) and major bleeding (HR 2.18, 95% CI 1.19–3.96). Conclusions: Cluster analysis identified four different clinically relevant phenotypes of AF patients that had unique clinical characteristics and different outcomes. Cluster analysis highlights the high degree of heterogeneity in patients with AF, suggesting the need for a phenotype-driven approach to comorbidities, which could provide a more holistic approach to management aimed to improve patients’ outcomes. Full article
(This article belongs to the Special Issue Aging, Inflammaging and Multimorbidity: What Is the Role of Endothelial Dysfunction?)
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Review

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24 pages, 21554 KiB  
Review
Endothelial Dysfunction in SARS-CoV-2 Infection
by Francesco Nappi and Sanjeet Singh Avtaar Singh
Biomedicines 2022, 10(3), 654; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10030654 - 11 Mar 2022
Cited by 10 | Viewed by 1989
Abstract
One of the hallmarks of the SARS-CoV-2 infection has been the inflammatory process that played a role in its pathogenesis, resulting in mortality within susceptible individuals. This uncontrolled inflammatory process leads to severe systemic symptoms via multiple pathways; however, the role of endothelial [...] Read more.
One of the hallmarks of the SARS-CoV-2 infection has been the inflammatory process that played a role in its pathogenesis, resulting in mortality within susceptible individuals. This uncontrolled inflammatory process leads to severe systemic symptoms via multiple pathways; however, the role of endothelial dysfunction and thrombosis have not been truly explored. This review aims to highlight the pathogenic mechanisms of these inflammatory triggers leading to thrombogenic complications. There are direct and indirect pathogenic pathways of the infection that are examined in detail. We also describe the case of carotid artery thrombosis in a patient following SARS-CoV-2 infection while reviewing the literature on the role of ACE2, the endothelium, and the different mechanisms by which SARS-CoV-2 may manifest both acutely and chronically. We also highlight differences from the other coronaviruses that have made this infection a pandemic with similarities to the influenza virus. Full article
(This article belongs to the Special Issue Aging, Inflammaging and Multimorbidity: What Is the Role of Endothelial Dysfunction?)
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24 pages, 2635 KiB  
Review
Endothelial Dysfunction in Pregnancy Complications
by Jakub Kornacki, Paweł Gutaj, Anastasia Kalantarova, Rafał Sibiak, Maurycy Jankowski and Ewa Wender-Ozegowska
Biomedicines 2021, 9(12), 1756; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9121756 - 24 Nov 2021
Cited by 11 | Viewed by 2534
Abstract
The endothelium, which constitutes the inner layer of blood vessels and lymphatic structures, plays an important role in various physiological functions. Alterations in structure, integrity and function of the endothelial layer during pregnancy have been associated with numerous gestational complications, including clinically significant [...] Read more.
The endothelium, which constitutes the inner layer of blood vessels and lymphatic structures, plays an important role in various physiological functions. Alterations in structure, integrity and function of the endothelial layer during pregnancy have been associated with numerous gestational complications, including clinically significant disorders, such as preeclampsia, fetal growth restriction, and diabetes. While numerous experimental studies have focused on establishing the role of endothelial dysfunction in pathophysiology of these gestational complications, their mechanisms remain unknown. Numerous biomarkers of endothelial dysfunction have been proposed, together with the mechanisms by which they relate to individual gestational complications. However, more studies are required to determine clinically relevant markers specific to a gestational complication of interest, as currently most of them present a significant overlap. Although the independent diagnostic value of such markers remains to be insufficient for implementation in standard clinical practice at the moment, inclusion of certain markers in predictive multifactorial models can improve their prognostic value. The future of the research in this field lies in the fine tuning of the clinical markers to be used, as well as identifying possible therapeutic techniques to prevent or reverse endothelial damage. Full article
(This article belongs to the Special Issue Aging, Inflammaging and Multimorbidity: What Is the Role of Endothelial Dysfunction?)
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