雷帕霉素靶蛋白信号通路在心脏生理学和疾病中的作用。

Mammalian target of rapamycin signaling in cardiac physiology and disease.

机构信息

From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ (S.S., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S., M.V.); and Division of Cardiology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University Sapienza, Rome, Italy (M.V.).

出版信息

Circ Res. 2014 Jan 31;114(3):549-64. doi: 10.1161/CIRCRESAHA.114.302022.

DOI:10.1161/CIRCRESAHA.114.302022

PMID:24481845

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3995130/

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.

摘要

哺乳动物雷帕霉素靶蛋白（mTOR）是一种非典型丝氨酸/苏氨酸激酶，通过与特定衔接蛋白相互作用形成 2 种不同的多蛋白复合物，即 mTOR 复合物 1（mTORC1）和 mTOR 复合物 2（mTORC2），从而发挥其主要的细胞功能。mTORC1 调节蛋白质合成、细胞生长和增殖、自噬、细胞代谢和应激反应，而 mTORC2 似乎调节细胞存活和极性。mTOR 通路在心血管生理学和病理学中发挥着关键的调节作用。然而，关于 mTOR 在心血管系统中的功能的大多数信息都与 mTORC1 在未受应激和应激心脏中的作用有关。mTORC1 是胚胎心血管发育和心脏结构和功能的出生后维持所必需的。此外，mTORC1 是心脏对压力超负荷的适应和代偿性肥大发展所必需的。然而，mTORC1 的部分和选择性药理学和遗传学抑制已被证明可以延长哺乳动物的寿命，减少由负荷增加或遗传性心肌病引起的病理性肥大和心力衰竭，减少急性和慢性心肌梗死后的心肌损伤，并减少由代谢紊乱引起的心脏紊乱。靶向 mTORC1 并增加心脏保护的最佳治疗策略正在深入研究中。本文综述了 mTOR 信号在心血管生理学和病理状态下发挥作用的相关信息。