mTOR SIGNALING IN DIABETES AND MYOCARDIAL INFARCTION



Anindita Das, Ph.D., Virginia Commonwealth University, Richmond, Virginia, USA

Mammalian target of rapamycin (mTOR), a conserved serine/threonine kinase, plays a crucial role in integrating cellular and environmental cues that modulate cell metabolism, growth, proliferation, survival and homeostasis. Deregulation of mTOR signaling has been implicated in many human diseases, including cancer, obesity, diabetes, pulmonary hypertension, cardiovascular diseases and neurodegeneration. Considering its pathophysiological importance, the mTOR signaling pathway has attracted broad scientific and clinical interest as a potential therapeutic target to treat a variety of diseases including patients with metabolic abnormalities and myocardial infarction. mTOR interacts with several proteins to form two functionally distinct complexes known as mTOR complex 1 (mTORC1) and complex 2 (mTORC2). There has been growing interest in investigating the role of mTOR inhibition in protecting the heart against ischemia/reperfusion (I/R) injury. Studies have shown that pharmacological inhibition of mTOR with rapamycin exerts preconditioning-like effect in the murine heart through activation of JAK-STAT3 signaling. Rapamycin attenuates cardiomyocyte necrosis and apoptosis as well as reduces tissue damage after myocardial infarction. mTOR inhibition prevents adverse cardiac remodeling and improves cardiac function following chronic myocardial infarction. Reperfusion therapy with rapamycin also protects the murine heart against I/R injury by selective activation of mTORC2 and ERK with concomitant inhibition of mTORC1 and p38. Moreover, a persistent hyper activation of mTORC1 has been implicated in obesity-related metabolic pathologies. Specific inhibition of mTORC1 activity with simultaneous activation of mTORC2 provides beneficial effect of cardioprotection in diabetic mouse heart. Chronic treatment with rapamycin improves metabolic status and prevents cardiac dysfunction in diabetic mice through attenuation of oxidative stress as well as alteration of contractile and glucose metabolic proteins. Rapamycin also protects diabetic mouse heart against myocardial reperfusion injury through STAT3 signaling. Therefore, selective targeting of mTOR subcomplexes may hold therapeutic promise to combat myocardial infarction and improve prognosis in diabetic patients.