Abnormal intracellular calcium release in heart failure

点击翻译按钮获取中文摘要

ABSTRACT Heart failure (HF) continuous to be a major health care challenge. Altered myocyte calcium (Ca) signaling is an essential part of the pathophysiology of HF and of critical relevance in the search for new effective therapies. Despite progress in the elucidation of Ca-dependent processes occurring on rapid time scales, mechanisms whereby Ca modulates slow cardiac processes, including long term adaptations to physiological and pathological stress, remain poorly understood. This critical barrier to progress is attributable to our poor understanding of foundational aspects of cardiomyocyte biology, including sites and mechanisms of protein synthesis, processing and delivery. This is compounded by the lack of technological tools for probing and tracking slower / long-lived molecular process in living myocytes. Store-operated Ca entry (SOCE), wherein depletion of intracellular Ca stores prompts extracellular Ca entry into the cytosol, has recently emerged as an important component of cardiomyocyte Ca signaling. SOCE is mediated by the stromal interaction molecule (STIM1), which, upon sensing sarco/endoplasmic reticulum (SR/ER) Ca depletion, interacts with and activates the sarcolemmal Ca- release activated channel protein (ORAI1). STIM1 has been reported to play a critical role in maladaptive hypertrophy. However, the mechanism whereby STIM1 contributes to hypertrophy and its role in adaptive hypertrophy (exercise-induced) remain to be elucidated. Recently, we discovered that SOCE and its molecular machinery are localized at the cell-to-cell contact sites, the intercalated discs (IDs). Based on preliminary results, we put forth a novel hypothesis that SOCE promotes myocyte longitudinal growth through facilitation of localized protein synthesis from a dedicated pool of mRNAs at the IDs. Indeed, SOCE in the normal heart may be optimally tuned to achieve a “Goldilocks zone” of adaptive hypertrophic response, as induced by exercise. In contrast, pathological dysregulation of SOCE may prove deleterious. Specifically, SOCE over-activity in disease may underlie maladaptive hypertrophy, thus leading to phenomena such as stress-induced cardiomyopathy (SCM). In this proposal, we will use cutting-edge cellular physiology and molecular techniques (including super- resolution microscopy, novel cellular reporter systems) and novel genetic mouse models to test these hypotheses and determine key cellular micro- and nanodomains, as well as molecular steps involved in SOCE- driven myocyte growth. We will also examine the possibility of targeting key components of the SOCE machinery (specifically, STIM1L, the long splice variant of STIM1) that mediate maladaptive hypertrophy. To this end, we propose the following specific aims: 1) Define the role of SOCE in adaptive and maladaptive hypertrophy. 2) Define subcellular and molecular mechanisms underlying modulation of hypertrophy by SOCE; and 3) Define the role and mechanism of SOCE in stress-induced hypertrophic cardiac disease. These studies will yield new insights into the mechanisms underlying physiological and pathological hypertrophy and provide a foundation for new mechanism-based therapies for abnormal cardiac structure and function.