Influence of the Cardiomyocyte Circadian Clock on Cardiac Hypertrophy

描述（由申请人提供）：尽管目前对慢性压力和/或容量超负荷诱导病理性肥大的分子机制的理解取得了明显进展，但肥厚型心肌病临床治疗的药理学策略仍然有限。为了促进最近的机制的见解翻译到临床环境中，目前的建议打算调查肥厚型心肌病在一个创新的维度。是时候了。阻塞性睡眠呼吸暂停和非浸渍型高血压患者发生肥厚性心肌病的风险增加，这与睡眠期心肌的不适当应激有关。相反，运动（在清醒/活动期间）导致心肌有益的生理生长。总的来说，这些观察结果使我们假设，一天中心肌受到肥大刺激的时间显著影响重塑反应。与这一假设一致，我们实验室的初步研究表明，异丙肾上腺素诱导心脏生长和肥大标志物（例如，ANF）在睡眠/非活动期开始时（相对于清醒/活动期开始时）给予小鼠时更大程度。关于机制，我们假设心肌细胞生物钟介导心脏对肥大刺激的时间依赖性反应。事实上，我们实验室的初步研究表明，在睡眠/非活动期开始时心肌细胞生物钟的暂时暂停（即，CCM和CBK小鼠）导致促肥大表型，在重量（例如，双心室重量），组织学（即，肌细胞横截面积），成像（例如，间隔壁厚度），和转录水平（例如，anf 和MCIP 1诱导）。这些观察结果导致了以下广泛的目标，这一建议：测试的创新假设，心肌细胞生物钟影响心脏的反应，病理和生理性肥大的刺激，在一天中的时间依赖性的方式，在转录，翻译后，和功能水平。我们计划通过完成以下具体目标（SA）来解决这个广泛的目标：SA 1-确定是否由心肌细胞昼夜节律钟介导的异丙肾上腺素依赖性病理性心室重构; SA 2-阐明心肌细胞昼夜节律钟是否调节心肌对生理性肥大生长的反应。成功完成拟议的研究不仅将揭示心肌细胞生物钟作为肥厚性重塑的新调节剂，而且还将强调在针对肥厚性心肌病临床治疗的不同分子机制时需要考虑时间。 公共卫生相关性：尽管在人类和动物模型中，许多诱导心脏肥大生长的因素以一天中的时间依赖性方式振荡，但相对较少的研究调查了肥大刺激的时间如何影响心室重构和收缩功能/功能障碍。目前的提案概述了旨在调查一天中心脏受到肥大刺激的时间是否显著影响生理与病理重塑的研究。完成拟议的研究将确定心肌细胞生物钟是否调节心脏对影响心脏功能/功能障碍的肥大刺激的反应性，并可能有助于解释为什么非浸渍型高血压和睡眠呼吸暂停患者表现出较差的临床结局。

DESCRIPTION (provided by applicant): Despite appreciable advances with regards to current understanding of the molecular mechanisms governing chronic pressure and/or volume overload induce pathologic hypertrophy, pharmacological strategies for the clinical treatment of hypertrophic cardiomyopathy remain limited. In order to facilitate translation of recent mechanistic insights to the clinical setting, the current proposal intends to investigate hypertrophic cardiomyopathy within an innovative dimension. That being time. Obstructive sleep apnea and non-dipping hypertensive patients have an increased risk for the development of hypertrophic cardiomyopathy, which is associated with an inappropriate stress of the myocardium during the sleep phase. Conversely, exercise bouts (during the awake/active period) result in beneficial, physiologic growth of the myocardium. Collectively, these observations led us to hypothesize that the time of day at which the myocardium is challenged with hypertrophic stimuli markedly influences the remodeling response. Consistent with this hypothesis, preliminary studies in our laboratory show that isoproterenol induced cardiac growth and expression of hypertrophic markers (e.g., anf) to a greater extent when administered to mice at the beginning of the sleep/inactive phase (relative to the beginning of the awake/active phase). Regarding mechanism, we hypothesize that the cardiomyocyte circadian clock mediates time-of-day-dependent responsiveness of the heart to hypertrophic stimuli. Indeed, initial studies in our laboratory show that temporal suspension of the cardiomyocyte circadian clock at the beginning of the sleep/inactive period (i.e., CCM and CBK mice) results in a pro-hypertrophic phenotype, at gravimetric (e.g., biventricular weight), histological (i.e., myocyte cross sectional area), imaging (e.g., septal wall thickness), and transcriptional levels (e.g., anf and mcip1 induction). These observations have led to the following broad objective of this proposal: to test the innovative hypothesis that the cardiomyocyte circadian clock influences the responsiveness of the heart to pathologic and physiologic hypertrophic stimuli in a time-of-day-dependent manner, at transcriptional, post-translational, and functional levels. We plan to address this broad objective through completion of the following specific aims (SA): SA1 - Determine whether time-of-day-dependent pathologic ventricular remodeling in response to isoproterenol is mediated by the cardiomyocyte circadian clock; and SA2 - Elucidate whether the cardiomyocyte circadian clock modulates responsiveness of the myocardium to physiological hypertrophic growth. Successful completion of the proposed studies will not only unveil the cardiomyocyte circadian clock as a novel regulator of hypertrophic remodeling, but will also highlight a need to consider time-of-day when targeting distinct molecular mechanisms for clinical treatment of hypertrophic cardiomyopathy. PUBLIC HEALTH RELEVANCE: Despite the fact that many factors that induce hypertrophic growth of the heart oscillate in a time-of-day- dependent manner in both humans and animal models, relatively few studies have investigated how the timing of hypertrophic stimuli influences ventricular remodeling and contractile function/dysfunction. The current proposal outlines studies designed to investigate whether the time of day at which the heart is challenged with a hypertrophic stimulus significantly influences physiological versus pathological remodeling. Completion of the proposed studies will establish whether the cardiomyocyte circadian clock modulates responsiveness of the heart to hypertrophic stimuli that influence heart function/dysfunction, and may help to explain why non- dipping hypertensive and sleep apnea patients exhibit poorer clinical outcomes.