Impact of Oxidative Stress on the Heart and Vasculature: Part 2 of a 3-Part Series

Abstract

Vascular disease and heart failure impart an enormous burden in terms of global morbidity and mortality. Although there are many different causes of cardiac and vascular disease, most causes share an important pathological mechanism: oxidative stress. In the failing heart, oxidative stress occurs in the myocardium and correlates with left ventricular dysfunction. Reactive oxygen species (ROS) negatively affect myocardial calcium handling, cause arrhythmia, and contribute to cardiac remodeling by inducing hypertrophic signaling, apoptosis, and necrosis. Similarly, oxidative balance in the vasculature is tightly regulated by a wealth of pro- and antioxidant systems that orchestrate region-specific ROS production and removal. Reactive oxygen species also regulate multiple vascular cell functions, including endothelial and smooth muscle cell growth, proliferation, and migration; angiogenesis; apoptosis; vascular tone; host defenses; and genomic stability. However, excessive levels of ROS promote vascular disease through direct and irreversible oxidative damage to macromolecules, as well as disruption of redox-dependent vascular wall signaling processes.

Keywords: cardiac; reactive oxygen species; vascular.

Figure 1. Mitochondrial ROS Generation in HF

In HF, the regulation of mitochondrial ROS emission is controlled by ion handling and mechanical workload. Increased myocyte workload and dysregulation of calcium (Ca²⁺) and sodium (Na⁺) handling reduce mitochondrial Ca²⁺ accumulation, causing NADH and NADPH oxidation. NADPH depletion provokes H₂O₂ emission from mitochondria. ANT = adenine nucleotide translocator; ADP = adenosine diphosphate; ATP = adenosine triphosphate; ATPase = adenosine triphosphatase; GPX = glutathione peroxidase; GR = glutathione reductase; GSH/GSSG = reduced/oxidized glutathione; HF = heart failure; H₂O₂ = hydrogen peroxide; IDH = isocitrate dehydrogenase; IMM = inner mitochondrial membrane; MCU = mitochondrial calcium uniporter; NADH = nicotinamide adenine dinucleotide; NADPH = nicotinamide adenine dinucleotide phosphate; NCLX = mitochondrial sodium/calcium (and lithium) exchanger; NNT = nicotinamide nucleotide transhydrogenase; O₂⁻ = superoxide; OMM = outer mitochondrial membrane; PRX = peroxiredoxin; ROS = reactive oxygen species; RyR = ryanodine receptor; SERCA = sarcoplasmic reticulum calcium adenosine triphosphatase; TR = thioredoxin reductase; TRXr/o = reduced/oxidized thioredoxin.

Figure 2. Efficacy of Hydralazine and Nitrates in HF

The combination of hydralazine and ISDN therapy is efficacious in the treatment of chronic HF with reduced ejection fraction. (Left) The powerful inhibitory effect of hydralazine on protein tyrosine nitration in rat smooth muscle cells by in situ generated ONOO⁻ (caused by 3-morpholino sydnonimine [SIN-1] administration) is illustrated. Reprinted, with permission, from Daiber et al. (46). (Right) The marked effect of combined ISDN + hydralazine (I/H) on survival in patients with HF and reduced left ventricular ejection fraction is illustrated, as demonstrated in the African-American Heart Failure (A-HeFT) Trial. Reprinted, with permission, from Taylor et al. (50). ISDN = isosorbide dinitrate;

Figure 3. Enzymes Determining Redox Balance Through Production or Scavenging of ROS

In the vasculature, O₂⁻ is generated by NADPH oxidase, xanthine oxidase, mitochondria, and uncoupled eNOS. Superoxide dismutase (SOD) converts O₂⁻ to H₂O₂. Through the Fenton reaction, H₂O₂ can spontaneously convert to the hydroxyl radical OH^•. Due to its extreme reactivity, OH^• can damage most cellular compartments. Immune cell–secreted myeloperoxidase (MPO) can mediate oxidation of chloride to hypochlorous acid (HOCl) using H₂O₂, and inactivate NO via oxidation to nitrite. By chlorination, HOCl inactivates multiple biomolecules, such as the eNOS substrate L-arginine and lipoproteins. The antioxidant enzymes glutathione (GSH) peroxidase, catalase, and peroxiredoxin convert H₂O₂ to oxygen and water. Paraoxonases (PON) 2 and 3 inhibit mitochondrial ROS production, whereas PON1 inhibits myeloperoxidase (MPO) and protects from oxidative stress mediated lipid-peroxidation. BH₄ = tetrahydrobiopterin; eNOS = endothelial nitric oxide synthase; NO = nitric oxide; Other abbreviations as in Figure 1.

Figure 4. ROS Mediate CVD in Response to Several Different Risk Factors

Vascular disease relates to a variety of pathological states, and is almost invariably prompted by classical and nonclassical risk factors. ROS play a central role in mediating the noxious effects of classical risk factors, and thus represent attractive therapeutic and preventive targets. CVD = cardiovascular disease; ROS = reactive oxygen species.

Figure 5. Mechanisms Through Which Cardiovascular Risk Factors Mediate Atherogenesis and Available Pharmacological Tools for Targeting Crucial Pathogenic Factors

Cardiovascular risk factors promote oxidative stress by stimulation of various pro-oxidant enzyme systems, tipping the redox balance in favor of oxidation, with O₂⁻ as the key mediator. Hypertension activates NADPH oxidase via angiotensin II (ATII) and angiotensin 1 receptor (AT1R) signaling. The main ROS sources in states of hypercholesterolemia are NADPH oxidase and xanthine oxidase (activated by oxidized low-density lipoprotein), and the hypercholesterolemia-mediated up-regulation of AT1R. Hyperglycemia, as seen in diabetes, associates primarily with mitochondrial ROS production, which can secondarily activate NADPH oxidase. Compounds contained in cigarette smoke activate NADPH oxidase, which mediates mitochondrial dysfunction and thus ROS production. Aging is associated with increased mitochondrial dysfunction and reduced eNOS activity. Superoxide from all sources can inactivate vasoprotective NO by its reaction to ONOO⁻, which, in turn, mediates uncoupling of eNOS-mediated oxygen reduction and NO⁻ production by oxidation of the essential cofactor tetrahydrobiopterin (BH₄). The enzymes dihydrofolate reductase (DHFR) and GTPCH1 counteract eNOS uncoupling by replenishing BH₄ levels via regeneration and de novo synthesis, respectively. ATII decreases BH₄ levels, not only by activating NADPH oxidase, but also by down-regulation of DHFR. NADPH oxidase has been seen to be inhibited by angiotensin-converting enzyme inhibitors (ACEIs), ATII receptor type 1 blockers (ARBs), 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), the β-blocker nebivolol, the plant-derived polyphenol resveratrol, and the organic nitrate pentaerithrityl tetranitrate (PETN). The same compounds inhibit eNOS uncoupling by activating GTPCH1 and DHFR. Mitochondrial O₂⁻ generation is decreased by ARBs, MitoQ and resveratrol. Other abbreviations as in Figures 1 and 3.

Central Illustration. Mechanisms, Sources, and Implications of Oxidative Stress in Cardiovascular Disease and Heart Failure

Aging, genetic predisposition, traditional risk factors, and environmental factors can induce oxidative stress, particularly in vessels, where nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and uncoupled nitric oxide synthase (NOS) are dominant sources. At physiological levels, a low increase in net reactive oxygen species (ROS) can induce protective effects through redox signaling mediating, for example, improved antioxidative capacity. If the generation of ROS outweighs antioxidative capacity, then at higher ROS levels cell damage and endothelial dysfunction arise, which contribute to the development of atherosclerosis. Through ischemia in the context of myocardial infarction (MI), this can induce the loss of functional myocardium and, eventually, heart failure. Although heart failure also arises via other mechanisms, including diabetes and primary cardiomyopathic processes, ultimately neuroendocrine activation via the renin-angiotensin-aldosterone system (RAAS) and angiotensin II receptor type 1 (AT₁-R), and the sympathetic nervous system (SNS), combined with increased pre- and after-load, impose additional oxidative stress on the heart. Specific mechanisms leading to increased cardiac oxidative stress then include receptor-induced activation of NOX2 and mitochondrial redox mismatch. As a consequence, oxidation of mitochondrial NADPH gives rise to hydrogen peroxide (H₂O₂), which plays a causal role in contractile dysfunction, arrhythmia, and ultimately maladaptive cardiac remodeling through hypertrophy and cell death. Potential points of intervention are through lifestyle change, exercise, and medication to reduce risk factors and environmental stressors. Medical options include hydralazine to improve endothelial function, angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARBs), and statins. More recently, drugs directly targeted to mitochondria have been developed, such as SS-31 or MitoQ, whose clinical efficacy is currently under evaluation. Ang II = angiotensin II; NO = nitric oxide.