Received for publication February 2, 2006.
Revised March 28, 2006.
Accepted for publication March 28, 2006.

Chronic -adrenergic Receptor Stimulation Induces Cardiac Apoptosis and Aggravates Myocardial Ischemia/Reperfusion Injury by Provoking iNOS-Mediated Nitrative Stress

Abstract

The present study provides the evidence that inducible nitric oxide synthase (iNOS)-mediated nitrative stress plays a pivotal role in chronic - adrenergic receptor (AR) stimulation induced cardiac damage. In mice, fourteen days of isoproterenol (ISO) stimulation via an osmotic mini-pump induced an upregulation of iNOS as evidenced by increases in mRNA, protein expression and immunochemical staining of myocardial iNOS. Serum level of C-reactive protein (CRP), an inflammatory mediator was also markedly increased. Under chronic ISO stimulation, the upregulated iNOS produced a significantly increased amount of nitric oxide (NO) and its by-product - peroxynitrite in the circulation and in the heart, and subsequently resulted in an accelerated myocardial apoptosis. 40 min myocardial ischemia (MI) and 24 hr reperfusion (R) further increased NO production and peroxynitrite formation, and resulted in an enlarged infarct size in the mice receiving chronic ISO stimulation. However, the treatment with a selective iNOS inhibitor-1400W or the use of a genetic modified animal - iNOS-KO mice markedly reduced iNOS-mediated production of NO and formation of peroxynitrite, consequently significantly decreased myocardial apoptosis and infarct size, demonstrating a crucial link between iNOS-mediated nitrative stress and myocardial injury. In conclusion, chronic -AR stimulation upregulates iNOS expression and increases NO production in the heart, which subsequently markedly enhances formation of reactive nitrogen species - peroxynitrite in the heart thereby elicits myocardial apoptosis and potentiates MI/R injury.

Key words: apoptosis, beta-adrenergic receptor, inducible nitric oxide synthase, myocardial ischemia, peroxynitrite, reactive nitrogen species