Abstract 15998: Leptin Modulates Cardiac Glucose Metabolism and Attenuates Injury in Acute Myocardial Infarction
Introduction In chronic myocardial infarction (MI), leptin improves survival, and limits structural and functional injury. It is unknown, however, what effect leptin has on cardiac metabolism and outcomes in acute MI. This study was thus performed to test the hypothesis that leptin signaling increases cardiac glucose metabolism and attenuates acute ischemic injury post-MI.
Methods/Results 12 week old male mice with (ObR+/+; n=36) and without (ObR-/-;n=36) genetic deletion of the leptin receptor were randomly assigned in equal numbers to experimental MI or sham procedure, and studied 3 days later by echocardiography and cardiac catheterization. Hearts were subsequently examined for biochemical and histologic measures of cardiac injury, and metabolism of glucose and fatty acids (FA). Results are presented as mean ± SEM with statistical comparisons by t-test. Groups of sham mice were not significantly different in any measured outcome. However, with MI, ObR-/- mice had greater cardiac dysfunction (fractional shortening 19.6±0.3 vs 31.1±0.1% and ejection fraction 23.9±2.1 vs 35.1±2.3%), and dilation (end diastolic dimension of 4.1±0.1 vs 3.7±0.1mm and end diastolic volume of 52.4±5.7 vs 46.5±2.5uL); all p<0.05. ObR-/- mice also had increased apoptosis by TUNEL (35±5 vs 10±1%; p<0.01), and oxidative stress by thiobarbituric reactive substances (7.1±0.7 vs 3.9±0.6 nMol/ml malondialdehyde equivalents; p<0.05). These worse indices of cardiac injury were associated with a 69±3% reduction in cardiac STAT-3 activation by Western blot (p<0.05). Further, rates of glycolysis (2.0±0.2 vs 4.4±0.2) and glucose oxidation (0.6±0.1 vs 1.7±0.2) were markedly depressed in ex vivo perfused ObR-/- hearts, whereas FA oxidation (0.40±0.04 vs 0.12±0.02) was markedly increased (all in uMol/min/g; all p<0.05). Moreover, the cardiac mRNA expression of glut4 was reduced 80±1% by qPCR in ObR-/- mice (p<0.01), and a shift from an intracellular (inactive) to a membrane bound (active) location was observed on immunofluroescent staining of cardiac sections from ObR+/+ mice.
Conclusions These data suggest that leptin modulates cardiac metabolism in favor of glucose in ischemic hearts, resulting in multiple improved structural and functional outcomes in acute MI.
- © 2011 by American Heart Association, Inc.