Chronic β-Adrenergic Receptor Stimulation Induces Cardiac Apoptosis and Aggravates Myocardial Ischemia/Reperfusion Injury by Provoking Inducible Nitric-Oxide Synthase-Mediated Nitrative Stress
- 30 March 2006
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Journal of Pharmacology and Experimental Therapeutics
- Vol. 318 (2), 469-475
- https://doi.org/10.1124/jpet.106.102160
Abstract
The present study provides evidence that inducible nitric-oxide synthase (iNOS)-mediated nitrative stress plays a pivotal role in chronic β-adrenergic receptor (AR) stimulation-induced cardiac damage. In mice, 14 days of isoproterenol (ISO) stimulation via an osmotic minipump induced an up-regulation of iNOS as evidenced by increases in mRNA, protein expression, and immunochemical staining of myocardial iNOS. Serum level of C-reactive protein, an inflammatory mediator, was also markedly increased. Under chronic ISO stimulation, the up-regulated iNOS produced a significantly increased amount of nitric oxide (NO) and its byproduct, peroxynitrite, in the circulation and heart and subsequently resulted in an accelerated myocardial apoptosis. Forty-minute myocardial ischemia (MI) and 24-h reperfusion (R) further increased NO production and peroxynitrite formation and resulted in an enlarged infarct size in mice receiving chronic ISO stimulation. However, the treatment with a selective iNOS inhibitor [N-(3-(aminomethyl) benzyl)acetamidine] (1400W) or the use of a genetic modified animal (iNOS-knockout mice) markedly reduced iNOS-mediated production of NO and formation of peroxynitrite and consequently significantly decreased myocardial apoptosis and infarct size, showing a crucial link between iNOS-mediated nitrative stress and myocardial injury. In conclusion, chronic β-AR stimulation up-regulates iNOS expression and increases NO production in the heart, which subsequently markedly enhances formation of reactive nitrogen species/peroxynitrite in the heart, thereby eliciting myocardial apoptosis and potentiating MI/R injury.Keywords
This publication has 31 references indexed in Scilit:
- Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia‐reperfusion injury and preconditioningBritish Journal of Pharmacology, 2003
- Regulation of nitric oxide production from macrophages by lipopolysaccharide and catecholaminesNitric Oxide, 2002
- Disruption of Inducible Nitric Oxide Synthase Improves β-Adrenergic Inotropic Responsiveness but Not the Survival of Mice With Cytokine-Induced CardiomyopathyCirculation Research, 2002
- Anti‐apoptotic effect of benidipine, a long‐lasting vasodilating calcium antagonist, in ischaemic/reperfused myocardial cellsBritish Journal of Pharmacology, 2001
- Beta adrenoceptor regulation of macrophage arginase activitySurgery, 2000
- On scientific languageJournal of Cardiac Failure, 2000
- β-Adrenergic Receptor Blockade in Chronic Heart FailureCirculation, 2000
- Cytokine-Mediated Apoptosis in Cardiac MyocytesCirculation Research, 1999
- The Major Receptor for C-Reactive Protein on Leukocytes Is Fcγ Receptor IIThe Journal of Experimental Medicine, 1999
- Induction of inflammatory cytokine release from cultured human monocytes by C-reactive proteinCytokine, 1992