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Oxidative Stress in Cardiovascular Diseases

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 32915

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Special Issue Editor

Dr. Nazha Hamdani

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Guest Editor

1. Institute of Physiology, Department Cellular and Translational Physiology, Ruhr University Bochum, Bochum, Germany
2. Institut für Forschung und Lehre (IFL) Molecular and Experimental Cardiology, Katholisches Klinikum Bochum, St. Josef-Hospital, Bochum, Germany
Interests: heart failure; molecular and experimental cardiology; cellular and translational physiology
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Dear Colleagues,

In practice, our limited understanding of heart failure (HF) means that we are unable to develop new and more effective treatment options for patients with this life-threatening condition. However, discoveries in basic research have advanced our understanding of disease mechanisms and have enabled the design of therapies that have reduced mortality to 40% in patients with systolic dysfunction. The traditional view of HF as a collection of signs and symptoms caused by inadequate performance of the heart leads to a narrow focus on only one aspect of the pathophysiology involved in the syndrome. A more modern view invokes a complex interaction of structural, functional, molecular, and biological alterations that account for the progressive nature of HF and help to explain the failure of large clinical trials to date. Metabolic disorders such as obesity, metabolic syndrome, and diabetes mellitus are major cardiovascular risk factors accompanied by increased risk of mortality, and are often associated with oxidative stress. Recent evidence indicates that oxidative stress may be the mechanistic link between obesity, diabetes mellitus, and related complications. Earlier failures to identify the underlying causes of disease explain disappointing clinical trial results and indicate that progress will not be possible until we disentangle symptoms from the causes. This lack of progress stems from our currently poor understanding of the central role of oxidative stress in HF and any beneficial effects in terms of therapy will require the targeting of this upstream modulator. Therefore, we aim to increase our basic understanding of the pathophysiology of heart diseases associated with oxidative stress, in order to provide firm foundations for clinical innovation.

The present Special Issue aims to collect and document new findings in the pathophysiology of natural heart diseases associated with oxidative stress and the effect of antioxidants to understand their application in heart failure.

Dr. Nazha Hamdani
Guest Editor

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Keywords

ROS and RNS signaling in heart disorders
oxidative stress and cardiac remodeling
redox signaling in cardiac myocytes
molecular mechanisms associated with the physiological responses to oxidative stress in heart failure
signaling pathway mechanisms in ROS and RNS generation
oxidative stress and cell signaling
protein oxidation in heart muscles
oxidative stress during myocardial ischemia/reperfusion and in heart failure
prevention and therapy
co-morbidities, aging, and oxidative stress
cardiomyocyte dysfunction
endothelial dysfunction
protein quality control and oxidative stress
cell-to-cell communication.

Published Papers (12 papers)

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16 pages, 14516 KiB

Open AccessArticle

Altered Cellular Protein Quality Control System Modulates Cardiomyocyte Function in Volume Overload-Induced Hypertrophy

by Kamilla Gömöri, Melissa Herwig, Roua Hassoun, Heidi Budde, Nusratul Mostafi, Simin Delalat, Suvasini Modi, Merima Begovic, Tamara Szabados, Judit Pipis, Nikolett Farkas-Morvay, István Leprán, Árpád Kovács, Andreas Mügge, Péter Ferdinandy, Anikó Görbe, Péter Bencsik and Nazha Hamdani

Antioxidants 2022, 11(11), 2210; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11112210 - 08 Nov 2022

Cited by 1 | Viewed by 1882

Abstract

Volume-induced hypertrophy is one of the risk factors for cardiac morbidity and mortality. In addition, mechanical and metabolic dysfunction, aging, and cellular redox balance are also contributing factors to the disease progression. In this study, we used volume overload (VO), which was induced by an aortocaval fistula in 2-month-old male Wistar rats, and sham-operated animals served as control. Functional parameters were measured by transthoracic echocardiography at termination 4- or 8-months after VO. The animals showed hypertrophic remodeling that was accompanied by mechanical dysfunction and increased cardiomyocyte stiffness. These alterations were reversible upon treatment with glutathione. Cardiomyocyte dysfunction was associated with elevated oxidative stress markers with unchanged inflammatory signaling pathways. In addition, we observed altered phosphorylation status of small heat shock proteins 27 and 70 and diminished protease expression caspases 3 compared to the matched control group, indicating an impaired protein quality control system. Such alterations might be attributed to the increased oxidative stress as anticipated from the enhanced titin oxidation, ubiquitination, and the elevation in oxidative stress markers. Our study showed an early pathological response to VO, which manifests in cardiomyocyte mechanical dysfunction and dysregulated signaling pathways associated with enhanced oxidative stress and an impaired protein quality control system. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Diseases)

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14 pages, 1787 KiB

Open AccessArticle

A Genotype–Phenotype Analysis of Glutathione Peroxidase 4 in Human Atrial Myocardium and Its Association with Postoperative Atrial Fibrillation

by Islam A. Berdaweel, Alexander A. Hart, Andrew J. Jatis, Nathan Karlan, Shahab A. Akhter, Marie E. Gaine, Ryan M. Smith and Ethan J. Anderson

Antioxidants 2022, 11(4), 721; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11040721 - 06 Apr 2022

Cited by 1 | Viewed by 2642

Abstract

Heterogeneity in the incidence of postoperative atrial fibrillation (POAF) following heart surgery implies that underlying genetic and/or physiological factors impart a higher risk of this complication to certain patients. Glutathione peroxidase-4 (GPx4) is a vital selenoenzyme responsible for neutralizing lipid peroxides, mediators of oxidative stress known to contribute to postoperative arrhythmogenesis. Here, we sought to determine whether GPX4 single nucleotide variants are associated with POAF, and whether any of these variants are linked with altered GPX4 enzyme content or activity in myocardial tissue. Sequencing analysis was performed across the GPX4 coding region within chromosome 19 from a cohort of patients (N = 189) undergoing elective coronary artery bypass graft (−/+ valve) surgery. GPx4 enzyme content and activity were also analyzed in matching samples of atrial myocardium from these patients. Incidence of POAF was 25% in this cohort. Five GPX4 variants were associated with POAF risk (permutated p ≤ 0.05), and eight variants associated with altered myocardial GPx4 content and activity (p < 0.05). One of these variants (rs713041) is a well-known modifier of cardiovascular disease risk. Collectively, these findings suggest GPX4 variants are potential risk modifiers and/or predictors of POAF. Moreover, they illustrate a genotype–phenotype link with this selenoenzyme, which will inform future mechanistic studies. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Diseases)

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15 pages, 2368 KiB

Open AccessArticle

Enhanced Cardiac CaMKII Oxidation and CaMKII-Dependent SR Ca Leak in Patients with Sleep-Disordered Breathing

by Michael Arzt, Marzena A. Drzymalski, Sarah Ripfel, Sebastian Meindl, Alexander Biedermann, Melanie Durczok, Karoline Keller, Julian Mustroph, Sylvia Katz, Maria Tafelmeier, Simon Lebek, Bernhard Flörchinger, Daniele Camboni, Sigrid Wittmann, Johannes Backs, Christof Schmid, Lars S. Maier and Stefan Wagner

Antioxidants 2022, 11(2), 331; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11020331 - 08 Feb 2022

Cited by 1 | Viewed by 1746

Abstract

Background: Sleep-disordered breathing (SDB) is associated with increased oxidant generation. Oxidized Ca/calmodulin kinase II (CaMKII) can contribute to atrial arrhythmias by the stimulation of sarcoplasmic reticulum Ca release events, i.e., Ca sparks. Methods: We prospectively enrolled 39 patients undergoing cardiac surgery to screen for SDB and collected right atrial appendage biopsies. Results: SDB was diagnosed in 14 patients (36%). SDB patients had significantly increased levels of oxidized and activated CaMKII (assessed by Western blotting/specific pulldown). Moreover, SDB patients showed a significant increase in Ca spark frequency (CaSpF measured by confocal microscopy) compared with control subjects. CaSpF was 3.58 ± 0.75 (SDB) vs. 2.49 ± 0.84 (no SDB) 1/100 µm⁻¹s⁻¹ (p < 0.05). In linear multivariable regression models, SDB severity was independently associated with increased CaSpF (B [95%CI]: 0.05 [0.03; 0.07], p < 0.001) after adjusting for important comorbidities. Interestingly, 30 min exposure to the CaMKII inhibitor autocamtide-2 related autoinhibitory peptide normalized the increased CaSpF and eliminated the association between SDB and CaSpF (B [95%CI]: 0.01 [−0.1; 0.03], p = 0.387). Conclusions: Patients with SDB have increased CaMKII oxidation/activation and increased CaMKII-dependent CaSpF in the atrial myocardium, independent of major clinical confounders, which may be a novel target for treatment of atrial arrhythmias in SDB. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Diseases)

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11 pages, 1757 KiB

Open AccessArticle

Aspirin Reduces Ischemia-Reperfusion Injury Induced Endothelial Cell Damage of Arterial Grafts in a Rodent Model

by Gábor Veres, Kálmán Benke, Roland Stengl, Yang Bai, Klára Aliz Stark, Alex Ali Sayour, Tamás Radovits, Sivakkanan Loganathan, Sevil Korkmaz-Icöz, Matthias Karck and Gábor Szabó

Antioxidants 2022, 11(2), 177; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11020177 - 18 Jan 2022

Cited by 2 | Viewed by 1580

Abstract

Long-term graft patency determines the prognosis of revascularization after coronary artery bypass grafting (CABG). Ischemia-reperfusion (I/R) injury of the graft suffered during harvesting and after implantation might influence graft patency. Aspirin, a nonsteroidal anti-inflammatory drug improves the long-term patency of vein grafts. Whether aspirin has the same effect on arterial grafts is questionable. We aimed to characterize the beneficial effects of aspirin on arterial bypass grafts in a rodent revascularization model. We gave Lewis rats oral pretreatment of either aspirin (n = 8) or saline (n = 8) for 5 days, then aortic arches were explanted and stored in cold preservation solution. The third group (n = 8) was a non-ischemia-reperfusion control. Afterwards the aortic arches were implanted into the abdominal aorta of recipient rats followed by 2 h of reperfusion. Endothelium-dependent vasorelaxation was examined with organ bath experiments. Immunohistochemical staining were carried out. Endothelium-dependent maximal vasorelaxation improved, nitro-oxidative stress and cell apoptosis decreased, and significant endothelial protection was shown in the aspirin preconditioned group, compared to the transplanted control group. Significantly improved endothelial function and reduced I/R injury induced structural damage were observed in free arterial grafts after oral administration of aspirin. Aspirin preconditioning before elective CABG might be beneficial on free arterial graft patency. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Diseases)

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20 pages, 4812 KiB

Open AccessArticle

Hsp22 Deficiency Induces Age-Dependent Cardiac Dilation and Dysfunction by Impairing Autophagy, Metabolism, and Oxidative Response

by Wenqian Wu, Xiaonan Sun, Xiaomeng Shi, Lo Lai, Charles Wang, Mingxin Xie, Gangjian Qin and Hongyu Qiu

Antioxidants 2021, 10(10), 1550; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10101550 - 29 Sep 2021

Cited by 6 | Viewed by 2203

Abstract

Heat shock protein 22 (Hsp22) is a small heat shock protein predominantly expressed in skeletal and cardiac muscle. Previous studies indicate that Hsp22 plays a vital role in protecting the heart against cardiac stress. However, the essential role of Hsp22 in the heart under physiological conditions remains largely unknown. In this study, we used an Hsp22 knockout (KO) mouse model to determine whether loss of Hsp22 impairs cardiac growth and function with increasing age under physiological conditions. Cardiac structural and functional alterations at baseline were measured using echocardiography and invasive catheterization in Hsp22 KO mice during aging transition compared to their age-matched wild-type (WT) littermates. Our results showed that Hsp22 deletion induced progressive cardiac dilation along with declined function during the aging transition. Mechanistically, the loss of Hsp22 impaired BCL-2–associated athanogene 3 (BAG3) expression and its associated cardiac autophagy, undermined cardiac energy metabolism homeostasis and increased oxidative damage. This study showed that Hsp22 played an essential role in the non-stressed heart during the early stage of aging, which may bring new insight into understanding the pathogenesis of age-related dilated cardiomyopathy. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Diseases)

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17 pages, 4007 KiB

Open AccessArticle

Pterostilbene Increases LDL Metabolism in HL-1 Cardiomyocytes by Modulating the PCSK9/HNF1α/SREBP2/LDLR Signaling Cascade, Upregulating Epigenetic hsa-miR-335 and hsa-miR-6825, and LDL Receptor Expression

by Yen-Kuang Lin, Chi-Tai Yeh, Kuang-Tai Kuo, Vijesh Kumar Yadav, Iat-Hang Fong, Nicholas G. Kounis, Patrick Hu and Ming-Yow Hung

Antioxidants 2021, 10(8), 1280; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10081280 - 12 Aug 2021

Cited by 9 | Viewed by 4328

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) can promote the degradation of low-density lipoprotein (LDL) receptor (LDLR), leading to hypercholesterolemia and myocardial dysfunction. The intracellular regulatory mechanism by which the natural polyphenol pterostilbene modulates the PCSK9/LDLR signaling pathway in cardiomyocytes has not been evaluated. We conducted Western blotting, flow cytometry, immunofluorescence staining, and mean fluorescence intensity analyses of pterostilbene-treated mouse HL-1 cardiomyocytes. Pterostilbene did not alter cardiomyocyte viability. Compared to the control group, treatment with both 2.5 and 5 μM pterostilbene significantly increased the LDLR protein expression accompanied by increased uptake of LDL. The expression of the mature PCSK9 was significantly suppressed at the protein and mRNA level by the treatment with both 2.5 and 5 μM pterostilbene, respectively, compared to the control. Furthermore, 2.5 and 5 μM pterostilbene treatment resulted in a significant reduction in the protein hepatic nuclear factor 1α (HNF1α)/histone deacetylase 2 (HDAC2) ratio and sterol regulatory element-binding protein-2 (SREBP2)/HDAC2 ratio. The expression of both hypoxia-inducible factor-1 α (HIF1α) and nuclear factor erythroid 2-related factor 2 (Nrf2) at the protein level was also suppressed. Pterostilbene as compared to short hairpin RNA against SREBP2 induced a higher protein expression of LDLR and lower nuclear accumulation of HNF1α and SREBP2. In addition, pterostilbene reduced PCSK9/SREBP2 interaction and mRNA expression by increasing the expression of hsa-miR-335 and hsa-miR-6825, which, in turn, increased LDLR mRNA expression. In cardiomyocytes, pterostilbene dose-dependently decreases and increases the protein and mRNA expression of PCSK9 and LDLR, respectively, by suppressing four transcription factors, HNF1α, SREBP2, HIF1α, and Nrf2, and enhancing the expression of hsa-miR-335 and hsa-miR-6825, which suppress PCSK9/SREBP2 interaction. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Diseases)

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26 pages, 5529 KiB

Open AccessArticle

The Interplay between S-Glutathionylation and Phosphorylation of Cardiac Troponin I and Myosin Binding Protein C in End-Stage Human Failing Hearts

by Heidi Budde, Roua Hassoun, Melina Tangos, Saltanat Zhazykbayeva, Melissa Herwig, Marharyta Varatnitskaya, Marcel Sieme, Simin Delalat, Innas Sultana, Detmar Kolijn, Kamilla Gömöri, Muhammad Jarkas, Mária Lódi, Kornelia Jaquet, Árpád Kovács, Hans Georg Mannherz, Vasco Sequeira, Andreas Mügge, Lars I. Leichert, Samuel Sossalla and Nazha Hamdani Show full author list Hide full author list

Antioxidants 2021, 10(7), 1134; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10071134 - 16 Jul 2021

Cited by 14 | Viewed by 3065

Abstract

Oxidative stress is defined as an imbalance between the antioxidant defense system and the production of reactive oxygen species (ROS). At low levels, ROS are involved in the regulation of redox signaling for cell protection. However, upon chronical increase in oxidative stress, cell damage occurs, due to protein, DNA and lipid oxidation. Here, we investigated the oxidative modifications of myofilament proteins, and their role in modulating cardiomyocyte function in end-stage human failing hearts. We found altered maximum Ca²⁺-activated tension and Ca²⁺ sensitivity of force production of skinned single cardiomyocytes in end-stage human failing hearts compared to non-failing hearts, which was corrected upon treatment with reduced glutathione enzyme. This was accompanied by the increased oxidation of troponin I and myosin binding protein C, and decreased levels of protein kinases A (PKA)- and C (PKC)-mediated phosphorylation of both proteins. The Ca²⁺ sensitivity and maximal tension correlated strongly with the myofilament oxidation levels, hypo-phosphorylation, and oxidative stress parameters that were measured in all the samples. Furthermore, we detected elevated titin-based myocardial stiffness in HF myocytes, which was reversed by PKA and reduced glutathione enzyme treatment. Finally, many oxidative stress and inflammation parameters were significantly elevated in failing hearts compared to non-failing hearts, and corrected upon treatment with the anti-oxidant GSH enzyme. Here, we provide evidence that the altered mechanical properties of failing human cardiomyocytes are partially due to phosphorylation, S-glutathionylation, and the interplay between the two post-translational modifications, which contribute to the development of heart failure. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Diseases)

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19 pages, 7317 KiB

Open AccessArticle

Integration of Cardiac Actin Mutants Causing Hypertrophic (p.A295S) and Dilated Cardiomyopathy (p.R312H and p.E361G) into Cellular Structures

by Constanze Erdmann, Roua Hassoun, Sebastian Schmitt, Carlos Kikuti, Anne Houdusse, Antonina J. Mazur, Andreas Mügge, Nazha Hamdani, Matthias Geyer, Kornelia Jaquet and Hans Georg Mannherz

Antioxidants 2021, 10(7), 1082; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10071082 - 05 Jul 2021

Cited by 4 | Viewed by 2235

Abstract

The human mutant cardiac α-actins p.A295S or p.R312H and p.E361G, correlated with hypertrophic or dilated cardiomyopathy, respectively, were expressed by the baculovirus/Sf21 insect cell system and purified to homogeneity. The purified cardiac actins maintained their native state but showed differences in Ca²⁺-sensitivity to stimulate the myosin-subfragment1 ATPase. Here we analyzed the interactions of these c-actins with actin-binding and -modifying proteins implicated in cardiomyocyte differentiation. We demonstrate that Arp2/3 complex and the formin mDia3 stimulated the polymerization rate and extent of the c-actins, albeit to different degrees. In addition, we tested the effect of the MICAL-1 monooxygenase, which modifies the supramolecular actin organization during development and adaptive processes. MICAL-1 oxidized these c-actin variants and induced their de-polymerization, albeit at different rates. Transfection experiments using MDCK cells demonstrated the preferable incorporation of wild type and p.A295S c-actins into their microfilament system but of p.R312H and p.E361G actins into the submembranous actin network. Transduction of neonatal rat cardiomyocytes with adenoviral constructs coding HA-tagged c-actin variants showed their incorporation into microfilaments after one day in culture and thereafter into thin filaments of nascent sarcomeric structures at their plus ends (Z-lines) except the p.E361G mutant, which preferentially incorporated at the minus ends. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Diseases)

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21 pages, 2887 KiB

Open AccessArticle

Interventricular Differences of Signaling Pathways-Mediated Regulation of Cardiomyocyte Function in Response to High Oxidative Stress in the Post-Ischemic Failing Rat Heart

by Árpád Kovács, Melissa Herwig, Heidi Budde, Simin Delalat, Detmar Kolijn, Beáta Bódi, Roua Hassoun, Melina Tangos, Saltanat Zhazykbayeva, Ágnes Balogh, Dániel Czuriga, Sophie Van Linthout, Carsten Tschöpe, Naranjan S. Dhalla, Andreas Mügge, Attila Tóth, Zoltán Papp, Judit Barta and Nazha Hamdani

Antioxidants 2021, 10(6), 964; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10060964 - 16 Jun 2021

Cited by 5 | Viewed by 2856

Abstract

Standard heart failure (HF) therapies have failed to improve cardiac function or survival in HF patients with right ventricular (RV) dysfunction suggesting a divergence in the molecular mechanisms of RV vs. left ventricular (LV) failure. Here we aimed to investigate interventricular differences in sarcomeric regulation and function in experimental myocardial infarction (MI)-induced HF with reduced LV ejection fraction (HFrEF). MI was induced by LAD ligation in Sprague–Dawley male rats. Sham-operated animals served as controls. Eight weeks after intervention, post-ischemic HFrEF and Sham animals were euthanized. Heart tissue samples were deep-frozen stored (n = 3–5 heart/group) for ELISA, kinase activity assays, passive stiffness and Ca²⁺-sensitivity measurements on isolated cardiomyocytes, phospho-specific Western blot, and PAGE of contractile proteins, as well as for collagen gene expressions. Markers of oxidative stress and inflammation showed interventricular differences in post-ischemic rats: TGF-β1, lipid peroxidation, and 3-nitrotyrosine levels were higher in the LV than RV, while hydrogen peroxide, VCAM-1, TNFα, and TGF-β1 were increased in both ventricles. In addition, nitric oxide (NO) level was significantly decreased, while FN-1 level was significantly increased only in the LV, but both were unchanged in RV. CaMKII activity showed an 81.6% increase in the LV, in contrast to a 38.6% decrease in the RV of HFrEF rats. Cardiomyocyte passive stiffness was higher in the HFrEF compared to the Sham group as evident from significantly steeper F_passive vs. sarcomere length relationships. In vitro treatment with CaMKIIδ, however, restored cardiomyocyte passive stiffness only in the HFrEF RV, but had no effect in the HFrEF LV. PKG activity was lower in both ventricles in the HFrEF compared to the Sham group. In vitro PKG administration decreased HFrEF cardiomyocyte passive stiffness; however, the effect was more pronounced in the HFrEF LV than HFrEF RV. In line with this, we observed distinct changes of titin site-specific phosphorylation in the RV vs. LV of post-ischemic rats, which may explain divergent cardiomyocyte stiffness modulation observed. Finally, Ca²⁺-sensitivity of RV cardiomyocytes was unchanged, while LV cardiomyocytes showed increased Ca²⁺-sensitivity in the HFrEF group. This could be explained by decreased Ser-282 phosphorylation of cMyBP-C by 44.5% in the RV, but without any alteration in the LV, while Ser-23/24 phosphorylation of cTnI was decreased in both ventricles in the HFrEF vs. the Sham group. Our data pointed to distinct signaling pathways-mediated phosphorylations of sarcomeric proteins for the RV and LV of the post-ischemic failing rat heart. These results implicate divergent responses for oxidative stress and open a new avenue in targeting the RV independently of the LV. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Diseases)

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19 pages, 11108 KiB

Open AccessArticle

Garcinol Attenuates Lipoprotein(a)-Induced Oxidative Stress and Inflammatory Cytokine Production in Ventricular Cardiomyocyte through α7-Nicotinic Acetylcholine Receptor-Mediated Inhibition of the p38 MAPK and NF-κB Signaling Pathways

by Nen-Chung Chang, Chi-Tai Yeh, Yen-Kuang Lin, Kuang-Tai Kuo, Iat-Hang Fong, Nicholas G. Kounis, Patrick Hu and Ming-Yow Hung

Antioxidants 2021, 10(3), 461; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10030461 - 16 Mar 2021

Cited by 17 | Viewed by 3494

Abstract

Garcinol, a nicotinic acetylcholine receptor (nAChR) antagonist, has recently been established as an anti-inflammation agent. However, the molecular mechanism by which garcinol suppresses inflammation in the context of acute myocardial infarction (AMI) remains unclear. Hypothesis: We hypothesized that the administration of physiological doses of garcinol in mice with isoproterenol-induced AMI decreased the effect of lipoprotein(a) (Lp(a))-induced inflammation both in vivo and in vitro via the α7-nAChRs mediated p38 mitogen-activated protein kinase (MAPK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathway. We analyzed altered reactive oxygen species (ROS) generation, the production of superoxide by mitochondria, cytokine expression patterns, and the role of the p38 MAPK/NF-κB signaling pathway after Lp(a)-stimulated human ventricular cardiomyocyte AC16 cells were treated with increasing doses of garcinol. C-reactive protein (CRP), interleukin (IL)-1β, IL-6, or tumor necrosis factor (TNF)-α production were detected by enzyme-linked immunosorbent assay. The Cell Counting Kit-8 assay was used to evaluate drug cytotoxicity. Western blots and confocal fluorescence microscopy were used to determine altered expression patterns of inflammatory biomarkers. We also examined whether the therapeutic effect of garcinol in AMI was mediated in part by α7-nAChR. Lp(a)-induced inflammatory cardiomyocytes had increased expression of membrane-bound α7-nAChRs in vitro and in vivo. Low-dose garcinol did not affect cardiomyocyte viability but significantly reduced mitochondrial ROS, CRP, IL-1β, IL-6, and TNF-α production in Lp(a)-stimulated cardiomyocytes (p < 0.05). The Lp(a)-induced phosphorylation of p38 MAPKs, CamKII, and NFκB, as well as NFκB-p65 nuclear translocation, was also suppressed (p < 0.05) by garcinol, while the inhibition of p38 MAPK by the inhibitor SB203580 decreased the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK. Garcinol protected cardiomyocytes by inhibiting apoptosis and inflammation in mice with AMI. Furthermore, garcinol also enhanced the expression of microRNA-205 that suppressed the α7-nAChR-induced p38 MAPK/NF-κB signaling pathway. Garcinol suppresses Lp(a)-induced oxidative stress and inflammatory cytokines by α7-nAChR-mediated inhibition of p38 MAPK/NF-κB signaling in cardiomyocyte AC16 cells and isoproterenol-induced AMI mice. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Diseases)

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17 pages, 9574 KiB

Open AccessArticle

A Novel Vasoactive Peptide “PG1” from Buffalo Ice-Cream Protects from Angiotensin-Evoked High Blood Pressure

by Albino Carrizzo, Manuela Giovanna Basilicata, Giacomo Pepe, Kasper K. Sørensen, Michele Ciccarelli, Veronica Di Sarno, Antonio Damato, Eleonora Venturini, Anna Borrelli, Simona Musella, Mario Abate, Paola Di Pietro, Carmine Ostacolo, Pietro Campiglia and Carmine Vecchione

Antioxidants 2021, 10(3), 441; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10030441 - 12 Mar 2021

Cited by 5 | Viewed by 2222

Abstract

Background: Arterial hypertension is the most important risk factor for cardiovascular diseases, myocardial infarction, heart failure, renal failure and peripheral vascular disease. In the last decade, milk-derived bioactive peptides have attracted attention for their beneficial cardiovascular properties. Methods: Here, we combined in vitro chemical assay such as LC-MS/MS analysis of buffalo ice cream, ex vivo vascular studies evaluating endothelial and smooth muscle responses using pressure myograph, and translational assay testing in vivo the vascular actions of PG1 administration in murine models. Results: We demonstrate that a novel buffalo ice-cream-derived pentapeptide “QKEPM”, namely PG1, is a stable peptide that can be obtained at higher concentration after gastro-intestinal digestions (GID) of buffalo ice-cream (BIC). It owns potent vascular effect in counteract the effects of angiotensin II-evoked vasoconstriction and high blood pressure levels. Its effects are mediated by the inhibitory effect on AT1 receptor leading to a downregulation of p-ERK½/Rac1-GTP and consequent reduction of oxidative stress. Conclusions: These results strongly candidate PG1, as a novel bioactive peptide for the prevention and management of hypertension, thus expanding the armamentarium of preventive strategies aimed at reducing the incidence and progression of hypertension and its related cardiovascular complications. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Diseases)

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Review

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Open AccessReview

Aging under Pressure: The Roles of Reactive Oxygen and Nitrogen Species (RONS) Production and Aging Skeletal Muscle in Endothelial Function and Hypertension—From Biological Processes to Potential Interventions

by Hollie Speer and Andrew J. McKune

Antioxidants 2021, 10(8), 1247; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10081247 - 04 Aug 2021

Cited by 6 | Viewed by 3136

Abstract

The proportion of adults living with hypertension increases significantly with advancing age. It is therefore important to consider how health and vitality can be maintained by the aging population until end of life. A primary risk factor for the progression of cardiovascular diseases (CVD) is hypertension, so exploring the factors and processes central to this burden of disease is essential for healthy aging. A loss of skeletal muscle quantity and quality is characteristic in normal aging, with a reduction of vasodilatory capacity caused by endothelial dysfunction, and subsequent increase in peripheral resistance and risk for hypertension. Reactive Oxygen and Nitrogen Species (RONS) encompass the reactive derivatives of NO and superoxide, which are continuously generated in contracting skeletal muscle and are essential mediators for cellular metabolism. They act together as intra and intercellular messengers, gene expression regulators, and induce programmed cell death. In excessive amounts RONS can inflict damage to endothelial and skeletal muscle cells, alter signaling pathways or prematurely promote stress responses and potentially speed up the aging process. The age-related increase in RONS by skeletal muscle and endothelial mitochondria leads to impaired production of NO, resulting in vascular changes and endothelial dysfunction. Changes in vascular morphology is an early occurrence in the etiology of CVDs and, while this is also a normal characteristic of aging, whether it is a cause or a consequence of aging in hypertension remains unclear. This review serves to focus on the roles and mechanisms of biological processes central to hypertension and CVD, with a specific focus on the effects of aging muscle and RONS production, as well as the influence of established and more novel interventions to mediate the increasing risk for hypertension and CVD and improve health outcomes as we age. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Diseases)

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Oxidative Stress in Cardiovascular Diseases

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