Mammalian target of rapamycin signaling in cardiac physiology and disease

Abstract

The protein kinase mammalian or mechanistic target of rapamycin (mTOR) is an atypical serine/threonine kinase that exerts its main cellular functions by interacting with specific adaptor proteins to form 2 different multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 regulates protein synthesis, cell growth and proliferation, autophagy, cell metabolism, and stress responses, whereas mTORC2 seems to regulate cell survival and polarity. The mTOR pathway plays a key regulatory function in cardiovascular physiology and pathology. However, the majority of information available about mTOR function in the cardiovascular system is related to the role of mTORC1 in the unstressed and stressed heart. mTORC1 is required for embryonic cardiovascular development and for postnatal maintenance of cardiac structure and function. In addition, mTORC1 is necessary for cardiac adaptation to pressure overload and development of compensatory hypertrophy. However, partial and selective pharmacological and genetic inhibition of mTORC1 was shown to extend life span in mammals, reduce pathological hypertrophy and heart failure caused by increased load or genetic cardiomyopathies, reduce myocardial damage after acute and chronic myocardial infarction, and reduce cardiac derangements caused by metabolic disorders. The optimal therapeutic strategy to target mTORC1 and increase cardioprotection is under intense investigation. This article reviews the information available regarding the effects exerted by mTOR signaling in cardiovascular physiology and pathological states.

Keywords: autophagy; heart; hypertrophy; ischemia; mechanistic target of rapamycin complex 1; metabolism; sirolimus.

Figure 1. General cellular functions of mTORC1 and mTORC2

This figure summarizes the most well characterized functions of mTORC1 and mTORC2. mTORC1 regulates protein synthesis and autophagy in response to growth factors and stress. mTORC2 is known to regulate cell growth, survival and polarity.

Figure 2. General overview of the mTOR signaling pathway

The Dashed line signifies that rapamycin inhibits mTORC2 in specific cell types or after prolonged treatment.

Figure 3. The role of mTOR in the regulation of cardiac homeostasis

mTOR is required for cardiomyocyte growth and for the preservation of cardiac structure and function in unstressed conditions. However, partial inhibition of mTOR appears to be beneficial during the aging process. The pharmacological modulators of mTOR and the animal models with genetic modifications of the components of the mTOR signaling pathway that have been used in the studies focused on the role of mTOR in cardiac physiology are displayed.

Figure 4. The role of mTOR in cardiac hypertrophy

mTOR activation promotes pathological hypertrophy during pressure overload. However, mTOR kinase is also required for physiological mechanisms that are necessary for cardiac adaptation to cardiac overload. The pharmacological modulators of mTOR and the animal models with genetic modifications of the components of the mTOR signaling pathway that have been used in the studies focused on the role of mTOR in cardiac hypertrophy are displayed.

Figure 5. The role of mTORC1 in ischemia-reperfusion

mTORC1 inhibition is protective during ischemia through the upregulation of adaptive mechanisms. On the other hand, mTOR is reactivated during reperfusion and takes part in the regulation of physiological processes. The pharmacological modulators of mTOR and the animal models with genetic modifications of the components of the mTOR signaling pathway that have been used in the studies focused on the role of mTOR in ischemia-reperfusion are displayed.

Figure 6. Cardiac mTORC1 activation in metabolic disorders

Cardiac mTORC1 activation contributes to cardiac abnormalities in obesity, metabolic syndrome and diabetes.