Role of oxidative-nitrosative stress and downstream pathways in various forms of cardiomyopathy and heart failure

Abstract

Heart failure is the major cause of hospitalization, morbidity and mortality worldwide. Previous experimental and clinical studies have suggested that there is an increased production of reactive oxygen species (ROS: superoxide, hydrogen peroxide, hydroxyl radical) both in animals and in patients with acute and chronic heart failure. The possible source of increased ROS in the failing myocardium include xanthine and NAD(P)H oxidoreductases, cyclooxygenase, the mitochondrial electron transport chain and activated neutrophils among many others. The excessively produced nitric oxide (NO) derived from NO synthases (NOS) has also been implicated in the pathogenesis of chronic heart failure (CHF). The combination of NO and superoxide yields peroxynitrite, a reactive oxidant, which has been shown to impair cardiac function via multiple mechanisms. Increased oxidative and nitrosative stress also activates the nuclear enzyme poly(ADP-ribose) polymerase (PARP), which importantly contributes to the pathogenesis of cardiac and endothelial dysfunction associated with myocardial infarction, chronic heart failure, diabetes, atherosclerosis, hypertension, aging and various forms of shock. Recent studies have demonstrated that pharmacological inhibition of xanthine oxidase derived superoxide formation, neutralization of peroxynitrite or inhibition of PARP provide significant benefit in various forms of cardiovascular injury. This review discusses the role of oxidative/nitrosative stress and downstream pathways in various forms of cardiomyopathy and heart failure.

Fig. 1. Proposed role of oxidative/nitrosative stress and downstream pathway in heart failure

Peroxynitrite, formed from superoxide and NO, causes cell injury via lipid peroxidation, inactivation of enzymes and other proteins by oxidation and nitration and also activation of matrix metalloproteinases (MMPs) just to mention a few. Peroxynitrite also triggers the release of proapoptotic factors such as cytochrome c and apoptosis inducing factor (AIF) from the mitochondria, which mediate caspase dependent and independent apoptotic death pathways. Peroxynitrite together with other oxidants, induces stand breaks in deoxyribonucleic acid (DNA), which in turn activates PARP. Mild damage of DNA activates the DNA repair machinery, but once excessive oxidative/nitrosative stress-induced damage occurs (like in various forms of myocardial reperfusion injury and heart failure), overactivated PARP initiates an energy-consuming cycle by transferring adenosine diphosphateribose units from nicotinamide adenine dinucleotide (NAD+) to nuclear proteins. This process will lead to depletion of the intracellular NAD+ and adenosine triphosphate (ATP) pools, slowing the rate of glycolysis and mitochondrial respiration, eventually culminating to cardiovascular dysfunction or death. Poly (ADP-ribose) glycohydrolase (PARG) degrades poly (ADP-ribose) (PAR) polymers, generating free PAR polymer and ADP-ribose. PARP also regulates the expression of a variety of inflammatory mediators, which may facilitate the progression of heart failure.

Fig. 2. Cardiac NADH concentration in dogs with pacing-induced heart failure

The heart was paced at 210 bpm for 3 weeks, and then the pacing rate was increased to 240 bpm until LV end-diastolic pressure reached 25 mm Hg and clinical signs of severe decompensation were observed (for details of the method see refs. 56,110). NADH content was measured by HPLC as we described [119,120]. Data are mean±S.E.M. (n=5 in each group). * p<0.05