Nitrosative stress and pharmacological modulation of heart failure.
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.
Pacher
Pal
P
Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane MSC 9413, Room 2S24, Bethesda, MD 20892-9413, USA. ppacher@lycos.com
Schulz
Richard
R
Liaudet
Lucas
L
Szabó
Csaba
C
D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000502:physiology; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000633:toxicity; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D011065:Poly(ADP-ribose) Polymerases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9