Targeting insulin signaling pathway to develop a new therapy for heart failure.

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To develop a new strategy that target insulin signaling, we examined a role of phosphoinositide 3-kinase (PI3K) or mammalian Target of Rapamycin (mTOR) in animal models of heart failure.1.Effect of rapamycin on a rat model of autoimmune myocarditis.We administered rapamycin, a selective inhibitor of mTOR, to rats immunized cardiac myosin. Rapamycin improved survival of the rats with autoimmune myocarditis. Rapamycin significantly reduced inflammation and fibrosis. Cardiac contractile function assessed by echocardiography was decreased in myosin immunized rats, and rapamycin preserved cardiac function. Rapamycin significantly attenuated autoimmune myocarditis of rats.2.Role of PI3K and mTOR in thyroid hormone induced cardiac hypertrophy.Hyperthyroidism causes cardiac hypertrophy and heart failure. We administered thyroid hormone to wild type mice or transgenic mice expressing dominant-negative PI3K specifically in cardiac muscle cells. Thyroid hormone increased heart weight by 27% in wi … More ld type mice. However, thyroid hormone increased heart weight of dominant-negative PI3K transgenic mice by 9%. We also administered rapamycin to thyroid hormone treated mice. Mice treated with thyroid hormone and rapamycin showed increase in heart weight by 9%. Thus, PI3K and mTOR are necessary for thyroid hormone induced cardiac hypertrophy in mice.3.Identification of target genes of rapamycin in growing mice hearts.We administered rapamycin or vehicle to one week old mice. The treatment was continued for a week and the mice were sacrificed. We compared the gene expression profiling using microarray analysis. Expressions of cyclin B3, eukaryotic translation initiation factor 3, stormal cell derived factor 2 like protein were decreased. Expressions of growth arrest specific gene 8, c-myc binding protein, autophagy 12-like protein were increased.In conclusion, rapamycin significantly attenuated cardiac hypertrophy and heart failure induced by myocarditis and hyperthyroidism. Rapamycin may be a therapeutic modality for heart failure. Less