Nitric Oxide and Oxidative Stress-Mediated Cardiovascular Functionality: From Molecular Mechanism to Cardiovascular Disease

The underlying pathology of most cardiovascular diseases (CVDs) such as coronary artery disease, high blood pressure, and stroke involves decreased cardiovascular contractility and anatomic alterations in cardiovascular structures. Nitric oxide (NO) regulates vascular tone and contractile function of myocardium and maintains blood vessel homeostasis. Interestingly, the effect of NO is like a double-edged sword in the body. Insufficient NO causes hypertension and atherosclerosis, while an overproduction of NO may foster inflammation and cause heart infarction and shock. In addition, growing evidences have shown that oxidative stress plays pivotal roles in the initiation and progression of CVDs. This chapter will discuss in detail the roles NO plays in the cardiovascular system under both physiological and pathological conditions. We will focus on: (1) the molecular mechanism of cardiovascular contraction, (2) NO/Ca2+-induced muscle relaxation, (3) NO-related structural change in blood vessels, and (4) redox balance in the cardiovascular system. The relationships between these molecular mechanisms and the characteristics of CVDs will be highlighted.

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Cellular and molecular mechanisms of statins: an update on pleiotropic effects

Clinical Science ◽

10.1042/cs20150027 ◽

2015 ◽

Vol 129 (2) ◽

pp. 93-105 ◽

Cited By ~ 54

Author(s):

Mamoru Satoh ◽

Yuji Takahashi ◽

Tsuyoshi Tabuchi ◽

Yoshitaka Minami ◽

Makiko Tamada ◽

...

Keyword(s):

Coronary Artery ◽

Chronic Inflammation ◽

Molecular Mechanism ◽

Coronary Atherosclerosis ◽

Molecular Mechanisms ◽

Cell Injury ◽

Plaque Instability ◽

Beneficial Effects ◽

Reductase Inhibitors ◽

Artery Disease

Coronary artery disease (CAD) is the leading cause of death worldwide. The efficacy and safety of statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) in primary and secondary prevention of CAD are confirmed in several large studies. It is well known that statins have some pleiotropic, anti-atherosclerotic effects. We review the molecular mechanisms underlying the beneficial effects of statins revealed in recently published studies. Endothelial cell injury is regarded as the classic stimulus for the development of atherosclerotic lesions. In addition, the inflammatory process plays an important role in the aetiology of atherosclerosis. In particular, chronic inflammation plays a key role in coronary artery plaque instability and subsequent occlusive thrombosis. Our previous reports and others have demonstrated beneficial effects of statins on endothelial dysfunction and chronic inflammation in CAD. A better understanding of the molecular mechanism underlying the effectiveness of statins against atherosclerosis may provide a novel therapeutic agent for the treatment of coronary atherosclerosis. The present review summarizes the cellular and molecular mechanism of statins against coronary atherosclerosis.

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Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00378.2014 ◽

2015 ◽

Vol 308 (4) ◽

pp. H291-H302 ◽

Cited By ~ 27

Author(s):

Niraj M. Bhatt ◽

Miguel A. Aon ◽

Carlo G. Tocchetti ◽

Xiaoxu Shen ◽

Swati Dey ◽

...

Keyword(s):

Oxidative Stress ◽

High Glucose ◽

Negative Impact ◽

Antioxidant Activities ◽

Contractile Function ◽

Heart Function ◽

Redox Balance ◽

The Impact ◽

Type 2 Diabetic

Hearts from type 2 diabetic (T2DM) subjects are chronically subjected to hyperglycemia and hyperlipidemia, both thought to contribute to oxidizing conditions and contractile dysfunction. How redox alterations and contractility interrelate, ultimately diminishing T2DM heart function, remains poorly understood. Herein we tested whether the fatty acid palmitate (Palm), in addition to its energetic contribution, rescues function by improving redox [glutathione (GSH), NAD(P)H, less oxidative stress] in T2DM rat heart trabeculae subjected to high glucose. Using cardiac trabeculae from Zucker Diabetic Fatty (ZDF) rats, we assessed the impact of low glucose (EG) and high glucose (HG), in absence or presence of Palm or insulin, on force development, energetics, and redox responses. We found that in EG ZDF and lean trabeculae displayed similar contractile work, yield of contractile work (Ycw), representing the ratio of force time integral over rate of O2 consumption. Conversely, HG had a negative impact on Ycw, whereas Palm, but not insulin, completely prevented contractile loss. This effect was associated with higher GSH, less oxidative stress, and augmented matrix GSH/thioredoxin (Trx) in ZDF mitochondria. Restoration of myocardial redox with GSH ethyl ester also rescued ZDF contractile function in HG, independently from Palm. These results support the idea that maintained redox balance, via increased GSH and Trx antioxidant activities to resist oxidative stress, is an essential protective response of the diabetic heart to keep contractile function.

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Nitric Oxide Synthetic Pathway in Patients with Microvascular Angina and Its Relations with Oxidative Stress

Oxidative Medicine and Cellular Longevity ◽

10.1155/2014/726539 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 7

Author(s):

Benedetta Porro ◽

Sonia Eligini ◽

Fabrizio Veglia ◽

Alessandro Lualdi ◽

Isabella Squellerio ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Pathological Condition ◽

No Synthase ◽

Microvascular Angina ◽

No Formation ◽

Oxidative Stress Status ◽

Patient Groups ◽

Artery Disease ◽

Reduced Forms

A decreased nitric oxide (NO) bioavailability and an increased oxidative stress play a pivotal role in different cardiovascular pathologies. As red blood cells (RBCs) participate in NO formation in the bloodstream, the aim of this study was to outline the metabolic profile of L-arginine (Arg)/NO pathway and of oxidative stress status in RBCs and in plasma of patients with microvascular angina (MVA), investigating similarities and differences with respect to coronary artery disease (CAD) patients or healthy controls (Ctrl). Analytes involved in Arg/NO pathway and the ratio of oxidized and reduced forms of glutathione were measured by LC-MS/MS. The arginase and the NO synthase (NOS) expression were evaluated by immunofluorescence staining. RBCs from MVA patients show increased levels of NO synthesis inhibitors, parallel to that found in plasma, and a reduction of NO synthase expression. When summary scores were computed, both patient groups were associated with a positive oxidative score and a negative NO score, with the CAD group located in a more extreme position with respect to Ctrl. This finding points out to an impairment of the capacity of RBCs to produce NO in a pathological condition characterized mostly by alterations at the microvascular bed with no significant coronary stenosis.

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Role of Oxidative Stress and Mitochondrial Dysfunction in Sepsis and Potential Therapies

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/5985209 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 53

Author(s):

Konstantinos Mantzarlis ◽

Vasiliki Tsolaki ◽

Epaminondas Zakynthinos

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Intensive Care ◽

Vitamin C ◽

Causes Of Death ◽

Redox Balance ◽

Cardiac Performance ◽

Efficiency Evaluation ◽

Permeability Impairment

Sepsis is one of the most important causes of death in intensive care units. Despite the fact that sepsis pathogenesis remains obscure, there is increasing evidence that oxidants and antioxidants play a key role. The imbalance of the abovementioned substances in favor of oxidants is called oxidative stress, and it contributes to sepsis process. The most important consequences are vascular permeability impairment, decreased cardiac performance, and mitochondrial malfunction leading to impaired respiration. Nitric oxide is perhaps the most important and well-studied oxidant. Selenium, vitamin C, and 3N-acetylcysteine among others are potential therapies for the restoration of redox balance in sepsis. Results from recent studies are promising, but there is a need for more human studies in a clinical setting for safety and efficiency evaluation.

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Regulation of the Proteolytic Activity of Cysteine Cathepsins by Oxidants

International Journal of Molecular Sciences ◽

10.3390/ijms21061944 ◽

2020 ◽

Vol 21 (6) ◽

pp. 1944 ◽

Cited By ~ 3

Author(s):

Gilles Lalmanach ◽

Ahlame Saidi ◽

Paul Bigot ◽

Thibault Chazeirat ◽

Fabien Lecaille ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Sulfhydryl Group ◽

Redox Balance ◽

Biological Functions ◽

Cysteine Cathepsins ◽

Michael Acceptors ◽

Natural Inhibitors

Besides their primary involvement in the recycling and degradation of proteins in endo-lysosomal compartments and also in specialized biological functions, cysteine cathepsins are pivotal proteolytic contributors of various deleterious diseases. While the molecular mechanisms of regulation via their natural inhibitors have been exhaustively studied, less is currently known about how their enzymatic activity is modulated during the redox imbalance associated with oxidative stress and their exposure resistance to oxidants. More specifically, there is only patchy information on the regulation of lung cysteine cathepsins, while the respiratory system is directly exposed to countless exogenous oxidants contained in dust, tobacco, combustion fumes, and industrial or domestic particles. Papain-like enzymes (clan CA, family C1, subfamily C1A) encompass a conserved catalytic thiolate-imidazolium pair (Cys25-His159) in their active site. Although the sulfhydryl group (with a low acidic pKa) is a potent nucleophile highly susceptible to chemical modifications, some cysteine cathepsins reveal an unanticipated resistance to oxidative stress. Besides an introductory chapter and peculiar attention to lung cysteine cathepsins, the purpose of this review is to afford a concise update of the current knowledge on molecular mechanisms associated with the regulation of cysteine cathepsins by redox balance and by oxidants (e.g., Michael acceptors, reactive oxygen, and nitrogen species).

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Nitric Oxide, Oxidative Stress, andp66ShcInterplay in Diabetic Endothelial Dysfunction

BioMed Research International ◽

10.1155/2014/193095 ◽

2014 ◽

Vol 2014 ◽

pp. 1-16 ◽

Cited By ~ 41

Author(s):

Alessandra Magenta ◽

Simona Greco ◽

Maurizio C. Capogrossi ◽

Carlo Gaetano ◽

Fabio Martelli

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Molecular Mechanisms ◽

Vascular Dysfunction ◽

Diabetic Patients ◽

Oxygen Species ◽

Complex Interplay ◽

Cell Dysfunction ◽

Intracellular Ros ◽

No Bioavailability

Increased oxidative stress and reduced nitric oxide (NO) bioavailability play a causal role in endothelial cell dysfunction occurring in the vasculature of diabetic patients. In this review, we summarized the molecular mechanisms underpinning diabetic endothelial and vascular dysfunction. In particular, we focused our attention on the complex interplay existing among NO, reactive oxygen species (ROS), and one crucial regulator of intracellular ROS production,p66Shcprotein.

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Cellular and Molecular Mechanisms of Nitric Oxide–Induced Heart Muscle Relaxation

General Pharmacology The Vascular System ◽

10.1016/s0306-3623(97)00302-9 ◽

1998 ◽

Vol 30 (4) ◽

pp. 543-553 ◽

Cited By ~ 15

Author(s):

K.V Azatian ◽

A.R White ◽

R.J Walker ◽

S.N Ayrapetyan

Keyword(s):

Nitric Oxide ◽

Heart Muscle ◽

Molecular Mechanisms ◽

Muscle Relaxation

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Molecular Mechanism of Arsenic-Induced Neurotoxicity including Neuronal Dysfunctions

International Journal of Molecular Sciences ◽

10.3390/ijms221810077 ◽

2021 ◽

Vol 22 (18) ◽

pp. 10077

Author(s):

Manisha Thakur ◽

Mahesh Rachamalla ◽

Som Niyogi ◽

Ashok Kumar Datusalia ◽

Swaran Jeet Singh Flora

Keyword(s):

Oxidative Stress ◽

Drinking Water ◽

Molecular Mechanism ◽

Molecular Mechanisms ◽

Arsenic Exposure ◽

Inorganic Arsenic ◽

Mitochondrial Oxidative Stress ◽

Neurological Effects ◽

Cellular Dna ◽

Neurobehavioral Effects

Arsenic is a key environmental toxicant having significant impacts on human health. Millions of people in developing countries such as Bangladesh, Mexico, Taiwan, and India are affected by arsenic contamination through groundwater. Environmental contamination of arsenic leads to leads to various types of cancers, coronary and neurological ailments in human. There are several sources of arsenic exposure such as drinking water, diet, wood preservatives, smoking, air and cosmetics, while, drinking water is the most explored route. Inorganic arsenic exhibits higher levels of toxicity compared its organic forms. Exposure to inorganic arsenic is known to cause major neurological effects such as cytotoxicity, chromosomal aberration, damage to cellular DNA and genotoxicity. On the other hand, long-term exposure to arsenic may cause neurobehavioral effects in the juvenile stage, which may have detrimental effects in the later stages of life. Thus, it is important to understand the toxicology and underlying molecular mechanism of arsenic which will help to mitigate its detrimental effects. The present review focuses on the epidemiology, and the toxic mechanisms responsible for arsenic induced neurobehavioral diseases, including strategies for its management from water, community and household premises. The review also provides a critical analysis of epigenetic and transgenerational modifications, mitochondrial oxidative stress, molecular mechanisms of arsenic-induced oxidative stress, and neuronal dysfunction.

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Abstract 357: Activation of Autophagic Flux Blunts Cardiac Ischemia/Reperfusion Injury

Circulation Research ◽

10.1161/res.121.suppl_1.357 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Geoffrey W Cho ◽

Min Xie ◽

Yongli Kong ◽

Dan L Li ◽

Xiang L Luo ◽

...

Keyword(s):

Oxidative Stress ◽

Infarct Size ◽

Reperfusion Injury ◽

Molecular Mechanisms ◽

Contractile Function ◽

Ischemia Reperfusion ◽

Neonatal Rat ◽

Border Zone ◽

Autophagic Flux ◽

Cardiomyocyte Autophagy

Background: Reperfusion injury accounts for a significant portion of myocardial damage in acute coronary syndromes. Autophagy, a process of cell catabolism, plays a vital role in the heart’s response to stress. We have reported that re-induction of ischemia/reperfusion (I/R)-suppressed cardiomyocyte autophagy with histone deacetylase (HDAC) inhibitors affords significant cardioprotection. However, as HDACs govern many processes and may have off-target effects, we set out to modulate autophagy in a manner independent of HDAC activity. Here, we hypothesized that induction of autophagy with a novel agent, Tat-Beclin, at the time of reperfusion, will reduce I/R injury and rescue cardiac function. Methods: Wild type and ATG7 (protein required for autophagic flux) knockout mice were randomized among 3 treatment groups prior to surgical I/R injury [45 min LAD artery ligation; 24h reperfusion]: vehicle control (VC), Tat-Scrambled (TS), or Tat-Beclin (TB). Each agent was delivered at coronary reperfusion. To define molecular mechanisms, cultured adult and neonatal rat ventricular cardiomyocytes (ARVMs/NRVMs) were subjected to simulated I/R. Results: Induction of cardiomyocyte autophagy at reperfusion reduced infarct size 20.1% (±6.3%, n=23, p<0.02 vs VC). This treatment was associated with improved systolic function (declines in fractional shortening: 19.8±3.7% VC; 18.7±2.1% TS; 8.5±1.7% TB, n=11, p<0.01 vs VC). In NRVMs subjected to I/R injury, cell death was reduced 41% (±6%, n=12, p<0.001 vs VC). Improvements correlated with increased autophagic flux measured by the marker LC3-II, particularly at the infarct border zone. Additional data suggested that autophagy rescues I/R injury through reduction of oxidative stress. ATG7 KO mice or NRVM depleted of ATG7 (RNAi) manifested significantly less cardioprotection. Conclusion: Direct induction of cardiomyocyte autophagy reduces infarct size and declines in contractile function. Autophagy rescues I/R injury in part through reduction of oxidative stress. Critically, this cardioprotection was observed when intervention occurred at the time of reperfusion, the clinically relevant context.

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