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/或容量超负荷导致病理性肥厚的分子机制的了解取得了显著进展，但肥厚型心肌病临床治疗的药物策略仍然有限。为了便于将最新的机械学见解转化到临床环境中，当前的提案打算在创新的维度内调查肥厚型心肌病。时间到了。阻塞性睡眠呼吸暂停和非降压性高血压患者患肥厚性心肌病的风险增加，这与睡眠期间心肌的不适当应激有关。相反，运动(在清醒/活跃期间)会带来有益的、生理性的心肌生长。总而言之，这些观察结果使我们假设，心肌在一天中受到肥厚刺激的时间显著影响重构反应。与这一假设一致，我们实验室的初步研究表明，异丙肾上腺素在小鼠睡眠/非活动期开始(相对于清醒/活动期开始)给药时，更大程度地诱导心脏生长和肥大标志物(例如ANF)的表达。在机制方面，我们假设心肌细胞的生物钟调节心脏对肥大刺激的依赖于时间的反应。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(即CCM和CBK小鼠)暂时暂停心肌细胞昼夜节律时钟会在重力(例如双室重)、组织学(即心肌细胞横截面积)、成像(例如隔壁厚度)和转录水平(例如ANF)导致促肥大表型 和mcip1诱导)。这些观察结果导致了这一提议的以下广泛目标：检验这一创新假设，即心肌细胞生物钟以一天中的时间依赖的方式在转录、翻译后和功能水平上影响心脏对病理和生理性肥厚刺激的反应。我们计划通过完成以下特定目标(SA)来解决这一广泛的目标：SA1-确定异丙肾上腺素反应中依赖时间的病理性心室重构是否由心肌细胞昼夜节律时钟介导；以及SA2-阐明心肌细胞昼夜节律时钟是否调节心肌对生理性肥大生长的反应。这些拟议研究的成功完成不仅将揭示心肌细胞生物钟作为肥厚性重构的新调节因素，而且还将突出在针对肥厚性心肌病临床治疗的不同分子机制时考虑时间的必要性。

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.