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HMG-CoA reductase inhibition protects the diabetic myocardium from ischemia-reperfusion injury¹

DAVID J. LEFER^*2, ROSARIO SCALIA, STEVEN P. JONES^*, BRENT R. SHARP^*, MICHAELA R. HOFFMEYER^*, ALI R. FARVID, MICHAEL F. GIBSON and ALLAN M. LEFER

^* Department of Molecular and Cellular Physiology, LSU Health Sciences Center, and
Department of Surgery, LSU Health Sciences Center, Shreveport, Louisiana 71130, USA; and
Department of Physiology, Thomas Jefferson University, Philadelphia, Pennsylvania

²Correspondence: Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Hwy., Shreveport, LA 71130, USA. E-mail: dlefer{at}lsuhsc.edu

SPECIFIC AIMS

We sought to determine whether acute treatment with simvastatin could enhance vascular nitric oxide (NO) production and attenuate the extent of myocardial ischemia-reperfusion injury in a murine model of type II diabetes mellitus independent of cholesterol reduction. We also investigated the potential anti-inflammatory effects of statin therapy on leukocyte–endothelial cell interactions in the diabetic microcirculation.

PRINCIPAL FINDINGS

1. Simvastatin augments endothelial NO synthase (NOS) mRNA levels and NO production
Treatment of diabetic mice with simvastatin (0.5 mg/kg/day) for 5 days significantly enhanced myocardial endothelial nitric oxide synthase (eNOS) mRNA levels compared with diabetic mice receiving vehicle. Basal vascular NO release was significantly depressed in diabetic mice that received vehicle compared with nondiabetic mice. However, administration of simvastatin augmented the level of NO production in the diabetic vasculature (Fig. 1 ).

View larger version (22K): [in this window] [in a new window]   Figure 1. Basal nitric oxide (NO) release (nmol/g tissue) from isolated segments of aorta in nondiabetic, diabetic, and diabetic mice treated with simvastatin. Basal NO release was significantly (P<0.01) reduced in diabetic animals compared with nondiabetic controls. Simvastatin treatment significantly (P<0.05) restored NO release in the diabetic aorta. Administration of the NO synthase inhibitor L-NAME completely abolished NO production in all study groups.

2. Simvastatin attenuates the extent of necrosis after ischemia and reperfusion of diabetic hearts in vivo
The area of myocardium placed at risk by left anterior descending coronary artery occlusion was similar in nondiabetic, diabetic, and diabetic hearts treated with simvastatin. However, myocardial necrosis was significantly increased in the diabetic mice compared with nondiabetics (Fig. 2 ). Treatment with simvastatin significantly reduced the extent of myocardial necrosis compared with diabetic mice injected with vehicle.

View larger version (32K): [in this window] [in a new window]   Figure 2. Myocardial area-at-risk per left ventricle (AAR/LV), area of necrosis per area-at-risk (NEC/AAR) in nondiabetic controls, diabetic mouse hearts, and diabetic hearts treated with simvastatin. Mice underwent 30 min of left anterior descending coronary artery ligation and 2 h of reperfusion. Myocardial area-at-risk per left ventricle was similar in all groups. Myocardial necrosis was significantly (P<0.02) increased in the diabetic mouse compared with nondiabetic control animals. The area of necrosis per area-at-risk was significantly (P<0.02) attenuated with simvastatin therapy.

3. Simvastatin diminishes the infiltration of neutrophils after ischemia and reperfusion in diabetic hearts
Myocardial neutrophil (PMN) infiltration in diabetic hearts after ischemia and reperfusion was significantly increased compared with nondiabetic hearts. Simvastatin treatment attenuated the extent of PMN infiltration in diabetic hearts after ischemia and reperfusion. These data are suggestive of an anti-inflammatory action of simvastatin in the diabetic vasculature.

4. Simvastatin exerts anti-inflammatory effects in the diabetic microvasculature by attenuating leukocyte–endothelium interactions
In additional studies, we ascertained whether simvastatin affected leukocyte–endothelial cell interactions in the diabetic mesenteric microvasculature. Basal white blood cell rolling was significantly enhanced in the diabetic microcirculation when compared with nondiabetic controls. Treatment of diabetic mice with simvastatin reduced white blood cell rolling to a level comparable to nondiabetic animals. White blood cell adhesion in the peri-intestinal microcirculation was increased by nearly fivefold in diabetic animals. Administration of simvastatin significantly decreased the extent of leukocyte adhesion in the diabetic mesenteric microcirculation.

CONCLUSION AND SIGNIFICANCE

Although diabetes mellitus adversely affects multiple organs, a significant portion of mortality in humans results from myocardial infarction. Diabetes mellitus predisposes individuals to more frequent and severe myocardial infarctions than observed in their nondiabetic peers. A large body of evidence indicates that endothelial cell NO production is attenuated in diabetes mellitus. Reductions in NO bioavailability secondary to endothelial dysfunction may contribute to vascular complications observed in various organs in diabetic patients. Normal endothelial cell function as measured by endothelial cell NO release is critical for the maintenance of cardiovascular homeostasis. It is now recognized that eNOS-derived NO is a potent inhibitor of leukocyte recruitment at sites of inflammation. Consequently, therapeutic interventions that promote NO production could be extremely important in attenuating the pathogenesis of cardiovascular diseases in diabetic patients. Our present study clearly supports such a possibility in a mouse model of diabetes mellitus.

We had previously demonstrated that simvastatin can attenuate ischemia-reperfusion injury in normal myocardium. However, the present study is the first investigation of the efficacy of simvastatin in myocardial ischemia-reperfusion injury in the setting of a clinically relevant risk factor (diabetes). The present data indicate that diabetic mice are characterized by attenuated vascular NO production. This results in increased leukocyte–endothelial cell interactions and an exacerbation in the extent of myocardial necrosis after ischemia and reperfusion. All of these findings occurred independent of alterations in serum cholesterol or glucose. Our results are supported by clinical observations of diabetic patients having more frequent endothelial dysfunction and myocardial infarction. These clinical findings are likely related to deficient NO production from the vascular endothelium of diabetic patients.

Previous studies have suggested that inflammation contributes to myocardial reperfusion injury. In addition, anti-leukocyte interventions reduce the extent of myocardial injury after coronary artery occlusion and reperfusion. In the present study, simvastatin markedly reduced the accumulation of neutrophils in the ischemic reperfused myocardium and attenuated leukocyte–endothelial cell interactions in the microcirculation of the diabetic mesentery. These findings are clearly indicative of anti-inflammatory effects of simvastatin that occurred independent of cholesterol reduction. These effects are likely related to enhanced NO production.

In summary, we provide novel insights into the potential therapeutic benefit of statins in acute coronary syndromes. Furthermore, our study may aid in explaining some cholesterol-independent benefits observed in diabetic patients treated with statins. Additional studies of the interactions among myocardial infarction, simvastatin, and other risk factors could further our understanding of these pathophysiologic phenomena. Present and future endeavors may ultimately expand the therapeutic indications for statins to diabetics with normal cholesterol levels.FIGURE 3

View larger version (68K): [in this window] [in a new window]   Figure 3. Scheme. Proposed mechanism of nitric oxide release after simvastatin treatment. The enhanced release of nitric oxide may account for the anti-inflammatory effects and attenuation of ischemia-reperfusion injury after simvastatin treatment. Although these pathways may involve steps in cholesterol metabolism, the protective effects of simvastatin in the present study occurred independent of cholesterol reduction. eNOS: endothelial nitric oxide synthase; NO: nitric oxide; PMN: neutrophil; ICAM-1: intercellular adhesion molecule-1; P: phosphorylation.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.00-0819fje ; to cite this article, use FASEB J. (April 27, 2001) 10.1096/fj.00-0819fje

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