The Role of Oxidative Stress in Cardiac Disease: From Physiological Response to Injury Factor

Table 1

Potential sources of ROS in the heart. There are multiple sources of ROS in the heart, including those arising from NADPH oxidase, xanthine oxidoreductase, nitric oxide synthases, monoamine oxidases, mitochondria, and cytochrome P450. Their role in generation of oxidative stress, how their activity is modulated, and the specific mechanisms of action are also described. BH₂: dihydrobiopterin; BH₄: tetrahydrobiopterin; CYP2E1: cytochrome P450 2E1; eNOS: endothelial NOS; ETC: electron transport chain; iNOS: inducible NOS; I/R: ischemia-reperfusion; LV: left ventricular; MAO: monoamine oxidases; NADPH: nicotinamide adenine dinucleotide phosphate hydrogen; NO: nitric oxide. NOSs: nitric oxide synthases; Nox: NADPH oxidases; nNOS: neuronal NOS; POAF: postoperative atrial fibrillation; PPARα: peroxisome proliferator-activated receptor alpha; ROS: reactive oxygen species; XDH: xanthine dehydrogenase; XO: xanthine oxidase; XOR: xanthine oxidoreductase.

NADPH oxidases (Nox)	(i) Nox catalyze the reduction of O2 to O2^- by using NADPH as electron donor.; (ii) Nox activity increases in the failing heart and in angiotensin-II-induced cardiac hypertrophy.; (iii) ROS produced by Nox can promote further ROS generation by other sources, such as XOR, and degrade BH4.; (iv) ROS generated by the Nox family of NADPH oxidases may act as second messengers regulating cell growth and differentiation.; (v) Suppression of Nox2 and Nox4 below physiological levels is able to exacerbate myocardial I/R injury, whereas a minimum level of ROS production by either Nox2 or Nox4 is essential for the activation of hypoxia-inducible factor-1α (HIF-1α) and inhibition of PPARα during I/R.; (vi) ROS specifically derived from the Nox2 NADPH oxidase give a relevant contribution to the development of cardiac remodeling associated with chemotherapy-induced cardiotoxicity.
Xanthine oxidoreductase (XOR)	(i) XDH and XO oxidate xanthine to uric acid promoting a flux of electrons to reduce NAD^+ to NADH (XDH) or O2 to H2O2 and O2^- (XR).; (ii) XDH/XO protein expression is increased in failing heart.; (iii) XO inhibition reverses LV remodeling and improves LV function in rats.
Mitochondrial ROS	(i) ROS generation is related to the partial reduction of O2 to O2^- by complexes I and III of the ETC and to the protein p66^shc.; (ii) Mitochondrial oxidant modifications attenuate cardiac aging, protect from cardiac disease, and prevent left ventricular remodeling and failure in animal models.; (iii) Complexes I and III are the best characterized enzyme complexes mediating ROS generation in the mitochondria and are responsible for the majority of mitochondrial ROS in cardiovascular physiology and disease.; (iv) Mitochondrial ROS are also generated by reverse electron transport at mitochondrial complex I.; (v) Mitochondrial ROS affect a broad range of cellular functions in the context of heart failure.; (vi) The increased mitochondrial calpain-1 is associated with mitochondrial ROS generation in diabetic cardiomyopathy.
NOSs	(i) NOSs catalyze the production of NO and citrulline from oxygen and L-arginine.; (ii) nNOS-derived NO may inhibit XOR activity, limiting myocardial oxidative stress and increasing NO availability within the myocardium.; (iii) iNOS upregulation and overexpression induce cardiac apoptosis, fibrosis, hypertrophy, and dilatation in animal models.; (iv) ROS generated by eNOS oxidize BH4 to BH2 and increase metalloproteinases activation.; (v) In the presence of high-glucose concentration, eNOS becomes unstable and electrons become diverted to molecular oxygen rather than to L-arginine, resulting in O2^- formation and leading to eNOS uncoupling.; (vi) Pressure overload triggers eNOS uncoupling, which in turn contributes to dilatory remodeling and cardiac dysfunction.; (vii) O2^- from Nox may activate XOR and degrade BH4 leading to NOS uncoupling, as observed in diabetes and hypertension.
Monoamine oxidases (MAO)	(i) MAO expression and their ability to produce ROS increase with age and in age-associated chronic diseases.; (ii) MAO activity is associated with an increased risk for POAF.; (iii) MAO-dependent oxidative stress also contributes to mast cell degranulation and cardiac fibrosis, ultimately resulting in diastolic dysfunction in type 1 diabetes.; (iv) MAO-A-induced oxidative stress triggers p53 activation and impairs lysosome function and acidification.; (v) Genetic deletion of MAO-A is protective in I/R injury, pressure overload, and heart failure.; (vi) Genetic deletion of MAO-B protects against oxidative stress, apoptosis, and ventricular dysfunction.
Cytochrome P450 oxidase	(i) CYP2E1 is among the most active CYPs in producing ROS.; (ii) The expression level of CYP2E1 increases significantly in human heart tissues under ischemia.; (iii) CYP2E1 is an important gene in the pathogenesis of dilated cardiomyopathy in animal models.; (iv) Marked expression of CYP2E is associated with several cellular markers of oxidative stress, including products of lipid peroxidation, and with increased cardiomyocytes apoptosis both in vitro and in vivo.
p66^shc	(i) p66^shc protein is a 66 kDa cytosolic protein encoded by the Shc gene that upon stress may translocate to mitochondria and accept electrons from cytochrome C resulting in the formation of H2O2.; (ii) Studies carried out by comparing hearts from p66^shc knockout and wild-type mice have highlighted the cardioprotective effects elicited by p66^shc ablation, since this protects against I/R insults.