Acute Reduction of Myocardial Infarct Size By a Hydroxymethyl Glutaryl Coenzyme A Reductase Inhibitor Is Mediated by Endothelial Nitric Oxide Synthase

Abstract

In addition to their lipid-lowering properties, statins improve endothelial function by increasing the activity of endothelial nitric oxide synthase (eNOS). It was hypothesized that, by this mechanism, statins protect the myocardium from ischemia/reperfusion injury in normocholesterolemic animals. Rats were pretreated for 1 week with either cerivastatin (0.3 mg/kg/d) or placebo. Anesthetized animals underwent 30 minutes of coronary artery occlusion (CAO) followed by 180 minutes of reperfusion. In a separate set of experiments, the NOS inhibitor l-NAME (15 mg/kg; N -nitro-l-arginine methyl ester) was administered 15 minutes before CAO. Cerivastatin decreased infarct size by 49% (P < 0.05) without reducing plasma cholesterol levels. Cerivastatin increased myocardial eNOS mRNA and NOS activity and by 52% and 58% (P < 0.05), respectively. Cardioprotection and upregulation of eNOS activity evoked by cerivastatin were not observed in rats cotreated with l-NAME. These results show that statins reduce the extent of myocardial necrosis in normocholesterolemic rats after acute ischemia/reperfusion injury by increasing myocardial eNOS activity. Therefore, statins may protect the heart not only by reducing the incidence of ischemic events, but also by limiting cell damage during acute myocardial infarction.

Early Administration of Fluvastatin, but not at the Onset of Ischemia or Reperfusion, Attenuates Myocardial Ischemia-Reperfusion Injury Through the Nitric Oxide Pathway Rather Than Its Antioxidant Property

“…4,6,7,[29][30][31] Those results were supported by data that the infarct-sparing effect of statins was not observed in eNOS-deficient mice 6 or with pretreatment with L-NAME, 7 a finding consistent with the present result. The mechanisms by which statins increase eNOS activity are related to their ability to stabilize eNOS mRNA 32 and/or to activate the PI3-kinase/Akt pathway.…”

“…3 Recent studies in experimental animals have demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) attenuate IR injury independently of their lipid-lowering action. [4][5][6][7][8] Statins have pleiotropic effects, including improvement of endothelial function by increased nitric oxide (NO) bioavailability, 9 and antioxidant 10 and antiinflammatory actions, 11 which may explain their attenuation of IR injury. The experimental result of cardioprotection by statins has therapeutic implication for patients with acute coronary syndrome who will be treated with reperfusion therapy; however, the time at which statin treatment was administered before IR varied from hours to days, and the Circulation Journal Vol.70, December 2006 results are conflicting.…”

Pravastatin Reduces Myocardial Infarct Size Via Increasing Protein Kinase C-Dependent Nitric Oxide, Decreasing Oxyradicals and Opening the Mitochondrial Adenosine Triphosphate-Sensitive Potassium Channels in Rabbits

“…17,18 Those results were supported by the finding that the infarct size-reducing effect of statins was not observed after pretreatment with L-NAME 19 or in the eNOS knockout mouse. 20 NO has been reported to increase coronary flow, 21 regulate the endothelial adhesiveness for monocyte, 22,23 inhibit platelet aggregation, 24,25 and deactivate neutrophils 26 and attenuate the activation of sympathetic nerve activity.…”

Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice

“…The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to decrease cardiovascular morbidity and mortality when administered before elective surgery or percutaneous coronary interventions (39), and recently, the American College of Cardiology/American Heart Association guidelines gave class IIa recommendation for the initiation of statin therapy before vascular surgery and class IIb recommendation for the initiation of statin therapy in patients with risk factors scheduled for intermediate risk surgery (21). Animal studies have shown that statins protect against ischemia-reperfusion injury and when administered before ischemia (2,5,7,31,32,46,48,49,54,55,59,62,63,68,69), or immediately upon reperfusion (4, 18, 62), limit myocardial infarct size (IS). The activation of eNOS is essential for the IS-limiting effects of late ischemic preconditioning (8,9,53,66).…”

“…The activation of eNOS is essential for the IS-limiting effects of late ischemic preconditioning (8,9,53,66). Similarly, several investigators have shown that the activation of Akt and endothelial NOS (eNOS) is essential for the myocardial protective effect of statins, since nonspecific NOS inhibitors blunt the IS-limiting effect of statins (5,63) and statins do not reduce IS in eNOS Ϫ/Ϫ mice (1,4,19,31,68,71). Inducible NOS (iNOS) activation is also essential for mediating the IS-limiting effects of statins.…”