Role of Oxidative Stress in Cardiac Hypertrophy and Remodeling

Abstract

C ardiac adaptation in response to intrinsic or external stress involves a complex process of chamber remodeling and myocyte molecular modifications. A fundamental response to increased biomechanical stress is cardiomyocyte and chamber hypertrophy. Although this may provide initial salutary compensation to the stress, sustained hypertrophic stimulation becomes maladaptive, worsening morbidity and mortality risks because of congestive heart failure and sudden death. 1 Growing evidence highlights oxidative and nitrosative stresses as important mechanisms for this maladaptation. [2][3][4][5][6][7][8][9] Oxidative stress occurs when excess reactive oxygen species (ROS) are generated that cannot be adequately countered by intrinsic antioxidant systems. Superoxide anion (O 2 Ϫ ) can further combine with NO, forming reactive compounds such as peroxynitrite, generating nitroso-redox imbalance. 4 ROS generation is a normal component of oxidative phosphorylation and plays a role in normal redox control of physiological signaling pathways. 5,8,9 However, excessive ROS generation triggers cell dysfunction, lipid peroxidation, and DNA mutagenesis and can lead to irreversible cell damage or death. 5,8,9 In this review, we discuss recent experimental evidence for the role of oxidant stress on cardiac remodeling, focusing on pressureoverload-induced hypertrophy and dilation. ROS, Antioxidant Enzymes, andNitroso-Redox Balance ROS include free radicals such as superoxide (O 2 Ϫ ) and hydroxyl radical and compounds such as hydrogen peroxide (H 2 O 2 ) that can be converted to radicals, and they participate in both normal and pathologic biochemical reactions. 9 O 2 Ϫ is formed intracellularly (Figure 1) by activation of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase or xanthine oxidase (XO), uncoupling of NO synthase (NOS), and electron transport and "leakage" during oxidative phosphorylation in the mitochondria. 5,8,9 H 2 O 2 can generate the highly reactive hydroxyl radical via Fenton chemistry under pathological conditions. 9 Cells also have intrinsic antioxidant systems that counter ROS accumulation. These include enzymes such as catalase, glutathione peroxidases, and superoxide dismutase, and nonenzymatic antioxidants, such as vitamins E, C, beta carotene, ubiquinone, lipotic acid, and urate. 9,10 Superoxide dismutase converts O 2 Ϫ to H 2 O 2 , which is further converted by catalase and glutathione peroxidase to water. The thioredoxin system, including thioredoxin, thioredoxin reductase, and NADPH, forms an additional integrated antioxidant defense system, which operates as a powerful protein-disulfide oxidoreductase. 10 -12 NO is another important reactive molecule controlling cardiovascular homeostasis. NO stimulates the synthesis of intracellular cGMP by activating soluble guanylyl cyclase, and cGMP and its target kinase cGK-1 (protein kinase G 1), in turn, modulate myocyte function, growth, and remodeling. 13 NO also interacts with proteins via S-nitrosylation at specific cysteine residues to alter their fu...

Novel mechanism of angiotensin II-induced cardiac injury in hypertensive rats: the critical role of ASK1 and VEGF

“…Accumulating evidence indicates that oxidative stress has a key role in the pathophysiology of heart failure. [18][19][20] Moreover, angiotensin II is well known to induce cardiovascular oxidative stress, which has a pivotal role in the mechanism of angiotensin II-induced cardiac injury. [18][19][20] Therefore, in this study, we also investigated the effects of tempol, a superoxide dismutase mimetic, in DS rats to elucidate the contribution of oxidative stress to cardiac injury.…”

“…[18][19][20] Moreover, angiotensin II is well known to induce cardiovascular oxidative stress, which has a pivotal role in the mechanism of angiotensin II-induced cardiac injury. [18][19][20] Therefore, in this study, we also investigated the effects of tempol, a superoxide dismutase mimetic, in DS rats to elucidate the contribution of oxidative stress to cardiac injury. We found that tempol had a similar role as irbesartan in the attenuation of LV oxidative stress, which then prevented cardiac hypertrophy, fibrosis, abnormalities in cardiac capillary density and endothelial apoptosis, which is mediated by VEGF and ASK1 in DS rats.…”

Protective Effects of Edaravone against Methamphetamine-Induced cardiotoxicity

“…Recently, several clinical and experimental studies revealed the evidences of the role of oxidative stress in cardiovascular disease such as heart failure. Excessive ROS production leads to oxidation of cellular proteins and lipids, and DNA damage and activation of intracellular signaling that finally could lead to initiation of cell death, which has been emerge as pathophysiological mechanism in a broad spectrum of cardiovascular diseases (9) . So far, no antidotes exist for the treatment of cardiac toxicity of METH use in various countries, so because of known important role of oxidative damage in cardiotoxic effects of METH, using an antioxidant may be helpful.…”

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

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