The Role And Mechanism Of Cardiac Insulin Resistance In The Development Of Heart Failure Coursed By Myocardial Hypertrophy

Objective： A rat model of heart failure induced by cardiac hypertrophy wasestablished to explore the role and mechanism of cardiac insulin resistance in thedevelopment of heart failure induced by myocardial hypertrophy, by studying theimpair of cardiac insulin sensitivity signal, the damage of mitochondrial oxidativesubstrates and mitochondrial dysfunction, etc..Method：A rat model of heart failure induced by cardiac hypertrophy was establishedby the constriction of abdominal aorta in SD rats.20weeks after the abdominal aortaconstriction, cardiac size and function were determined by echocardiography.Hyperinsulin-euglycemic clamp was used to evaluate the systemic insulin sensitivityof the rats. glucose and fatty acid oxidation rate as well as their changes under thestimulus of insulin were measured in the isolated working heart. The proteinexpression of p38mitogen-activated protein kinase(MAPK) was evaluated byWestern blotting. Electronic microscope was used for researches of mitochondrialinjury, then evaluate the extent of the injuries.Result：20weeks after the abdominal aorta constriction, the rats had obviousmyocardial hypertrophy and cardiac systolic and diastolic dysfunction. The basalglucose oxidation was normal, but the fatty acid oxidation was obviously reduced.Insulin’s effect on oxidation substrate was significantly impaired for both the decreasein fatty acid oxidation and the increase in glucose oxidation. Thehyperinsulin-euglycemic clamp showed that the systemic glucose utilization wasnormal, suggesting the cardiac IR existed separately from systemic IR. The proteinexpression of p38mitogen-activated protein kinase was significantly reduced. Underthe electron microscope, the mitochondria in hypertrophy myocardial cells revealed seriously damaged.Conclusion：Cardiac insulin resistance caused by cardiac hypertrophy at the level ofpartial substrate oxidation, was associated with mitochondrial damage and cardiacsystolic and diastolic dysfunction. Mitochondrial damage reflected in the decreasecapacity of glucose and fatty acid oxidation, possibly caused by mitochondrialbiosynthesis disorders induced by a decrease in the expression of p38MAPK. Thecardiac insulin resistance existed separately from systemic insulin resistance whichwas a risk factor for heart failure.