Influence of the Cardiomyocyte Circadian Clock on Cardiac Hypertrophy

描述（由申请人提供）：尽管目前对控制慢性压力和/或容量过载诱导病理性肥厚的分子机制的理解有了明显的进展，但肥厚性心肌病临床治疗的药理学策略仍然有限。为了促进将最近的机制见解转化为临床环境，目前的建议打算在创新的维度内研究肥厚性心肌病。那就是时间。阻塞性睡眠呼吸暂停和非浸入性高血压患者发生肥厚性心肌病的风险增加，肥厚性心肌病与睡眠阶段心肌的不适当应激有关。相反，运动回合（在清醒/活动期间）会导致有益的心肌生理性生长。总的来说，这些观察结果使我们假设一天中心肌受到肥厚刺激的时间显著影响重构反应。与这一假设相一致，我们实验室的初步研究表明，异丙肾上腺素在小鼠睡眠/非活动期开始时（相对于清醒/活动期开始）更大程度上诱导心脏生长和肥厚标志物（如anf）的表达。关于机制，我们假设心肌细胞生物钟介导心脏对肥厚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（即CCM和CBK小鼠）开始时，心肌细胞生物钟的时间暂停会导致在重量（如双心室重量）、组织学（如心肌细胞横截面积）、成像（如间隔壁厚度）和转录水平（如心肌细胞密度）上的促肥厚表型

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.