Nitrosative stress and pharmacological modulation of heart failure - PubMed (original) (raw)

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Nitrosative stress and pharmacological modulation of heart failure

Pal Pacher et al. Trends Pharmacol Sci. 2005 Jun.

Abstract

Dysregulation of nitric oxide (NO) and increased oxidative and nitrosative stress are implicated in the pathogenesis of heart failure. Peroxynitrite is a reactive oxidant that is produced from the reaction of nitric oxide with superoxide anion and impairs cardiovascular function through multiple mechanisms, including activation of matrix metalloproteinases (MMPs) and nuclear enzyme poly(ADP-ribose) polymerase (PARP). Recent studies suggest that the neutralization of peroxynitrite or pharmacological inhibition of MMPs and PARP are promising new approaches in the experimental therapy of various forms of myocardial injury. In this article, the role of nitrosative stress and downstream mechanisms, including activation of MMPs and PARP, in various forms of heart failure are discussed and novel emerging therapeutic strategies offered by neutralization of peroxynitrite and inhibition of MMPs and PARP in these pathophysiological conditions are reviewed.

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Figures

Figure 1

Figure 1

Progression of heart failure and the role of oxidative and nitrosative stress. The mechanisms that lead to heart failure are of multiple origins and include acute and chronic ischemic heart disease, cardiomyopathies, myocarditis and pressure overload. These diseases result in a mismatch between the load applied to the heart and the energy needed for contraction, leading to mechanoenergic uncoupling. Following initial insult, secondary mediators such as angiotensin II (Ang II), noradrenaline (NA), endothelin (ET) and pro-inflammatory cytokines [e.g. tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6)], in concert with oxidative and nitrosative stress, act directly on the myocardium or indirectly via changes in hemodynamic loading conditions to cause endothelial and myocardial dysfunction, cardiac and vascular remodeling with hypertrophy, fibrosis, cardiac dilation and myocardial necrosis, leading eventually to heart failure. The adverse remodeling and increased peripheral resistance further aggravate heart failure. Abbreviations: MMP, matrix metalloproteinase; PARP, poly(ADP-ribose) polymerase.

Figure 2

Figure 2

Proposed role of the oxidative and nitrosative stress–poly(ADP-ribose) polymerase 1 (PARP-1) pathway in oxidant-induced cellular dysfunction and necrosis. Nitric oxide (NO) and superoxide (O2‐) (derived from NADPH oxidase, mitochondria, xanthine oxidase and catechol oxidation) react to form peroxynitrite (ONOO−), which induces cell damage via lipid peroxidation, inactivation of enzymes and other proteins by oxidation and nitration, and activation of matrix metalloproteinases (MMPs) among others (a) (Table 1). Peroxynitrite also acts on mitochondria [decreasing the membrane potential (Ψ)], triggering the release of pro-apoptotic factors such as cytochrome c (Cyt c) and apoptosis-inducing factor (AIF) (b). These factors mediate caspase-dependent and caspase-independent apoptotic death pathways, respectively. Moreover, peroxynitrite, in concert with other oxidants [e.g. hydrogen peroxide (H2O2)], causes strand breaks in DNA, activating PARP-1 (c). Mild damage to DNA activates the DNA repair machinery. By contrast, once excessive oxidative and nitrosative stress-induced DNA damage occurs, as in various forms of myocardial reperfusion injury and heart failure, overactivated PARP-1 initiates an energy-consuming cycle by transferring ADP-ribose units (small orange spheres) from NAD+ to nuclear proteins, resulting in rapid depletion of the intracellular NAD+ and ATP pools, slowing the rate of glycolysis and mitochondrial respiration, and eventually leading to cellular dysfunction and death. Poly (ADP-ribose) glycohydrolase (PARG) degrades poly(ADP-ribose) (PAR) polymers, generating free PAR polymer and ADP-ribose. PARP-1 also regulates the expression of a variety of inflammatory mediators, which might facilitate the progression of heart failure.

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