mTOR in growth and protection of hypertrophying myocardium.
mTOR in growth and protection of hypertrophying myocardium.
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DOI：
10.2174/187152509787047603
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发表时间：
2009-01
影响因子：
--
通讯作者：
Kuppuswamy D
中科院分区：
文献类型：
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作者：
Balasubramanian S;Johnston RK;Moschella PC;Mani SK;Tuxworth WJ Jr;Kuppuswamy D
心脏肥大作为一种适应性机制，对血流动力学负荷增加（如压力或容量超负荷）作出反应。虽然肥厚最初维持心室功能，但在此过程中尚未明确的脱轨最终导致功能受损（代偿失调），并最终以充血性心力衰竭（CHF）告终。因此，确定在代偿性生长过程中诱导的分子特征对于描述负责向CHF转变的特定机制是重要的。补偿性增长涉及多个过程。在心肌细胞水平，一个主要事件是蛋白质周转增加，其中增强的蛋白质合成伴随着有害蛋白质的去除增加。许多介导蛋白质周转的途径依赖于一个关键分子，即哺乳动物雷帕霉素靶蛋白（mTOR）。在压力超负荷心肌中，已知肾上腺素能受体、生长因子受体和整合素以PI 3 K依赖性和/或非依赖性方式激活mTOR，并涉及特异性PKC亚型。被描述为细胞营养和能量状态的传感器的mTOR被独特地定位为通过雷帕霉素敏感和不敏感的信号传导模块激活调节翻译、细胞大小和泛素-蛋白酶体系统（UPS）的途径。雷帕霉素敏感复合物，称为mTOR复合物1（mTORC 1），由mTOR、mTOR的雷帕霉素敏感衔接蛋白（Raptor）和mLST 8组成，并通过S6 K1等分子促进蛋白质翻译和细胞大小。雷帕霉素不敏感复合物（mTORC 2）由mTOR、mLST 8、mTOR的雷帕霉素不敏感伴侣（Rictor）、mSin 1和Protor组成。mTORC 2除了激活Akt（蛋白激酶B）以随后通过UPS去除促凋亡因子以使细胞存活之外，还调节肌动蛋白细胞骨架。在这篇综述中，我们讨论了介导肥大心肌细胞生长和存活的mTOR复合物的途径和关键靶点，以及mTOR抑制剂雷帕霉素的治疗潜力。
In response to an increased hemodynamic load, such as pressure or volume overload, cardiac hypertrophy ensues as an adaptive mechanism. Although hypertrophy initially maintains ventricular function, a yet undefined derailment in this process eventually leads to compromised function (decompensation) and eventually culminates in congestive heart failure (CHF). Therefore, determining the molecular signatures induced during compensatory growth is important to delineate specific mechanisms responsible for the transition into CHF. Compensatory growth involves multiple processes. At the cardiomyocyte level, one major event is increased protein turnover where enhanced protein synthesis is accompanied by increased removal of deleterious proteins. Many pathways that mediate protein turnover depend on a key molecule, mammalian target of rapamycin (mTOR). In pressure-overloaded myocardium, adrenergic receptors, growth factor receptors, and integrins are known to activate mTOR in a PI3K-dependent and/or independent manner with the involvement of specific PKC isoforms. mTOR, described as a sensor of a cell’s nutrition and energy status, is uniquely positioned to activate pathways that regulate translation, cell size, and the ubiquitin-proteasome system (UPS) through rapamycin-sensitive and -insensitive signaling modules. The rapamycin-sensitive complex, known as mTOR complex 1 (mTORC1), consists of mTOR, rapamycin-sensitive adaptor protein of mTOR (Raptor) and mLST8 and promotes protein translation and cell size via molecules such as S6K1. The rapamycin-insensitive complex (mTORC2) consists of mTOR, mLST8, rapamycin-insensitive companion of mTOR (Rictor), mSin1 and Protor. mTORC2 regulates actin cytoskeleton in addition to activating Akt (Protein kinase B) for the subsequent removal of proapoptotic factors via the UPS for cell survival. In this review, we discuss pathways and key targets of mTOR complexes that mediate growth and survival of hypertrophying cardiomyocytes and the therapeutic potential of mTOR inhibitor, rapamycin.