Unraveling the complexities of cardiac remodeling and hypertrophy - high-content screening and computational modeling.
Unraveling the complexities of cardiac remodeling and hypertrophy - high-content screening and computational modeling.
复制标题
揭示心脏重塑和肥大的复杂性 - 高内涵筛查和计算建模。
DOI：
10.1016/j.yjmcc.2014.03.014
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发表时间：
2014
影响因子：
5
通讯作者：
vanBerlo,JopH
中科院分区：
文献类型：
--
作者：
Elrod,JohnW;vanBerlo,JopH
在稳态条件下，大多数哺乳动物的心脏重量与体重直接相关[1]。然而，已经发现许多刺激和压力会引起心肌生长、增加心脏大小和重塑心室形状。怀孕和锻炼等生理刺激会导致心脏体积增大，并伴随心输出量增加，这是完全可逆的，与以后生活中的不良事件无关。另一方面，人们长期以来一直认识到许多分子信号会引起肥大和重塑，最初可以被认为是应对急性损伤的积极反应，但随着持续的信号传导变得适应不良。许多应激源与病理性心脏肥大/重塑有关，包括：主动脉瓣狭窄、严重二尖瓣关闭不全、基因突变、高血压和心肌梗塞，其中远端心肌必须补偿心肌细胞丢失的区域[2]。导致心肌细胞肥大和重塑的信号传导途径已被广泛研究，导致从配体/受体信号传导水平到一系列第二信号通路的复杂分子途径。信使，到聚合转录程序的翻译后途径。使用还原论方法，通常结合药物制剂和功能获得/功能丧失实验系统，无数研究为设计巨大比例的心脏重塑通路树做出了贡献，这已成为最近评论的主题[3-5]。然而，我们传统的线性实验方法虽然范围广泛且冗余，但在很大程度上未能定义区分生理重塑和病理重塑的确切信号模式[6, 7]。此外，目前尚不清楚生理性肥大如何完全发生。
Heart weight directly correlates with body weight in most mammals under homeostatic conditions [1]. However, numerous stimuli and stresses have been found to elicit myocardial growth, increase heart size, and remodel ventricular shape. Physiological provocations, such as pregnancy and exercise, result in an increase in heart size accompanied by enhanced cardiac output that is completely reversible and not related to adverse events later in life. On the other hand, it has been appreciated for some time that numerous molecular signals elicit hypertrophy and remodeling that initially could be considered a positive response to cope with an acute insult, but with persistent signaling become maladaptive. Numerous stressors have been implicated in pathological cardiac hypertrophy/remodeling including: aortic valve stenosis, severe mitral valve regurgitation, genetic mutations, hypertension and myocardial infarction, where the remote myocardium must compensate for the lost region of cardiomyocytes [2].The signaling pathways that lead to cardiomyocyte hypertrophy and remodeling have been extensively studied, resulting in complex molecular pathways from the level of ligand/receptor signaling through a host of second messengers, to post-translational pathways converging on transcriptional programs. Using a reductionist approach, often incorporating pharmacologic agents and gain-/loss-of-function experimental systems, countless studies have contributed to the design of a cardiac remodeling pathway tree of enormous proportions that has been the subject of recent reviews [3–5]. However, our traditionally linear experimental approaches, while expansive and redundant in scope, have largely failed to define the exact signaling patterns that distinguish physiological from pathological remodeling [6, 7]. Further, it remains unknown how physiological hypertrophy is completely