Abstract 1618: Role of Nitric Oxide in Regulation of Myocardial Glucose Metabolism; A Potential Mechanism of Cardioprotection
Ischemia induces a switch in myocardial substrate utilization from fatty acids to glucose and stimulates nitric oxide (NO) production. Although increased NO synthesis can ameliorate ischemic injury, mechanism by which NO confers cardioprotection remains unclear. Based on our recent observation that increased NO production contributes to ischemic activation of aldose reductase (AR), we tested the hypothesis that NO prevents ischemic injury by increasing reduction of glucose to sorbitol via polyol pathway over its oxidation to lactate in glycolysis, that could prevent acidosis. Our data show that in isolated mouse hearts subjected to 30 min of ischemia, sorbitol levels increased from 43.2 ± 2.4 to 68.7 ± 4.6 nmol/mg (n=6; P < 0.05) and returned to pre-ischemic levels after 30 min of reperfusion. Treatment with eNOS agonist, bradykinin (10 μM), prior to ischemia, increased AR activity from 27.5 ± 0.7 to 35.9 ± 1.4 mU/mg (n=6; P < 0.01) and decreased lactate levels from 3.7 ± 0.6 to 1.5 ± 0.4 mM (n=6; P < 0.05) upon reperfusion. Bradykinin also decreased creatine kinase (CK) and lactate dehydrogenase (LDH) release by 65 ± 7% and 85 ± 9%, respectively. In contrast, NOS inhibitor, L-NAME (0.1 mM) decreased AR activity (22.4 ± 2.0 mU/mg), but increased the activity of glyceraldehyde-3-phosphate dehydrogenase (from 2.4 ± 0.1 to 3.5 ± 0.2 U/mg) and lactate production (5.8 ± 0.9 mM). AR inhibitor, sorbinil (0.1 mM) increased lactate production (5.9 ± 0.1 mM) and exacerbated ischemic injury. Pretreatment with bradykinin normalized lactate levels and reduced injury caused by sorbinil. To examine whether upregulation of AR is sufficient to confer cardioprotection, cardio-specific AR transgenic mice were generated. Echocardiography confirmed, that these mice had normal myocardial function and when subjected to 30 min of coronary occlusion followed by 24 h of reperfusion displayed reduced myocardial infarct size (49.6 ± 4.1 vs 64.6 ± 3.5 % of the area at risk; transgenic vs wild type; n=7; P < 0.01). Collectively, these results show that NO mediates cardioprotection by increasing glucose flux via polyol pathway, which may represent an adaptive mechanism protecting the heart from ischemic injury.
This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).