Chronic β-Adrenergic Receptor Stimulation Induces Cardiac Apoptosis and Aggravates Myocardial Ischemia/Reperfusion Injury by Provoking Inducible Nitric-Oxide Synthase-Mediated Nitrative Stress

Abstract

The present study provides 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, 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 (iNOSknockout 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 ␤-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 eliciting myocardial apoptosis and potentiating MI/R injury.

Tomato lycopene attenuates myocardial infarction induced by isoproterenol: Electrocardiographic, biochemical and anti–apoptotic study

“…Further increase in nitrosative stress and reactive oxygen species production led to an enlarged infarct size in the ISO injected MI [30] . The present study showed a significant increase in the percentage of infarction in ISO injected rats.…”

“…Group I rats received distilled water and olive oil (vehicle for LYP) for 30 days and normal saline (1 mL/kg, s.c.) on the 29th and 30th day. Group II rats received distilled water and olive oil for 30 days and ISO (200 mg/kg, s.c.) in normal saline on the 29th and 30th day at an interval of 24 h. Group III rats received LYP (10 mg/kg/day, p.o.) for 30 days.…”

“…The heart was transversely cut across the left ventricle to obtain slices no more than 0.1 cm in thickness. The heart slices were placed in the covered, darkened glass dish containing pre warmed (1%) TTC solution in phosphate buffer and the dish was incubated between 37-40 曟 for [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] min. the heart slices were turned over once or twice to make certain that it remains immersed and covered by 1 cm of the TTC solution.…”

Evidence for Preoperative Aspirin Improving Major Outcomes in Patients With Chronic Kidney Disease Undergoing Cardiac Surgery

“…Thirdly, beta-adrenergic receptor blockers, due to their inherent role in blocking sympathetic activation, have been shown to reduce perioperative ischemia and the risk of MI and death in high-risk surgical patients (9,18,19). Fourthly, coronary plaque disruption is found in more than half of fatal perioperative MIs and considered as a primary cause of fatal perioperative MI (20)(21)(22) or chronic β-adrenergic activation provokes proinflammatory and proapoptotic changes in the mouse heart, indicating a close link between stress hormone (catecholamines) and inflammatory reaction, a key mechanism to provoke plaque rupture(s) (23,24). Nevertheless, persistent myocardial ischemia secondary to coronary spasm, hypotension and arrhythmias may also result in MACE in some patients undergoing surgery (Figure).…”

How to prevent perioperative myocardial injury: The conundrum continues

“…Finally, our recent study demonstrated that chronic catecholamine stimulation can aggravate myocardial injury by provoking inflammatory reaction and increasing myocardial apoptosis, thereby illustrating a mechanistic link between extreme/prolonged surgical stress → catecholamine release → inflammation/myocardial apoptosis and PMI. 8 Nevertheless, coronary plaque disruption was found in more than half of fatal perioperative myocardial infarctions and was considered as a primary cause of fatal perioperative myocardial infarction. 9,10 More likely, surgery, especially major surgery with its associated trauma, anesthesia, pain, bleeding, and hypothermia, is comparable to an extreme stress test, thereby producing a triggering/provoking effect in the pathogenesis of PMI (ie, inflicting inflammation and destabilizing plaques) and ultimately leading to appearance of PMI.…”