Chronic beta-adrenergic receptor stimulation induces cardiac apoptosis and aggravates myocardial ischemia/reperfusion injury by provoking inducible nitric-oxide synthase-mediated nitrative stress.
The present study provides evidence that inducible nitric-oxide synthase (iNOS)-mediated nitrative stress plays a pivotal role in chronic beta-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 beta-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.
Department of Anesthesiology, Suite G8490, 111 South 11th Street, Philadelphia, PA 19107, USA.
Aihua
A
Hu
Xiangying
X
Jiao
Erhe
E
Gao
Walter J
WJ
Koch
Said
S
Sharifi-Azad
Zvi
Z
Grunwald
Xin L
XL
Ma
Jian-Zhong
JZ
Sun
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002097:C-Reactive Protein; D006321:Heart / Q000187:drug effects*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007545:Isoproterenol / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology*; D009206:Myocardium / Q000166:cytology* / Q000201:enzymology; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis; D013312:Stress, Physiological / Q000503:physiopathology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D009566:Nitrates; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D012313:RNA; D002097:C-Reactive Protein; D052247:Nitric Oxide Synthase Type II; D007545:Isoproterenol