Beta Adrenergic Receptors and Focal Adhesion Cross-talk in Cardiac Remodeling

描述（由申请方提供）：在心脏中，通过儿茶酚胺刺激b-肾上腺素能受体（b-AR）是一种强大的调节机制，可增强心肌对应激或运动的反应。然而，B- AR的持续激活损害心肌细胞收缩性并诱导心肌细胞凋亡，从而导致心力衰竭（HF）。尽管广泛接受细胞收缩功能障碍和b-AR诱导的HF是相互关联的，但涉及的分子机制仍然知之甚少。整合素和粘着斑（FA）都作为连接细胞外基质（ECM）与细胞骨架蛋白的附着位点，并且对于维持收缩装置的结构完整性以及心肌细胞的生长和存活是必需的。我们发现，早期诱导的离心性肥大反应容量超负荷（VO）的压力诱导受损的FA信号与增强间质胶原降解和心肌细胞凋亡。当动物用b1-AR阻滞剂治疗时，这些变化显著减少。体内b1-AR信号传导的某些方面，包括FA信号传导下调，细胞骨架重排和心肌细胞凋亡，可以在体外使用b1-AR激动剂刺激的新生大鼠心肌细胞（NRCM）重现。FA信号的恢复足以阻断b1-AR诱导的心肌细胞凋亡。这导致了这样的假设，即急性VO应激反应中的b1- AR刺激通过改变FA信号促进心肌细胞凋亡。目的1：探讨持续刺激b1-AR诱导NRCM中FA信号下调的分子机制。目的2将确定在b1-AR诱导的心肌细胞凋亡过程中，FA复合物下游导致启动caspase激活的信号通路。最后，目的3将确定是否b1-AR诱导的FA信号的改变参与心肌细胞凋亡和心脏重构，以响应VO的血流动力学应激。拟议的研究将整合FA信号在b1-AR诱导的心肌细胞收缩功能障碍和凋亡中的新作用，这可能导致VO诱导的HF期间有害的心脏重塑。了解这些方法如何实现其效果将最终为开发人类HF的新疗法提供最大的动力。公共卫生相关性β-肾上腺素能受体在心脏的神经体液调节和心力衰竭的进展中发挥核心作用。拟开展的研究将整合黏着斑信号在β-肾上腺素能受体诱导的心肌细胞收缩功能障碍和心肌细胞凋亡中的新作用，这些可能导致心力衰竭。了解这些方法如何实现其效果将为开发人类心力衰竭的新疗法提供最大的动力。

DESCRIPTION (provided by applicant): In the heart, b-adrenergic receptors (b-AR) stimulation by catecholamines is a powerful regulatory mechanism that enhances myocardial performance in response to stress or exercise. However, sustained activation of b- AR impairs cardiac myocyte contractility and induces myocyte apoptosis, thus leading to heart failure (HF). Despite widespread acceptance that cellular contractile dysfunction and b-AR-induced HF are inter-related, the molecular mechanisms involved remain poorly understood. Integrins and focal adhesions (FA) both serve as attachment sites linking extracellular matrix (ECM) to cytoskeleton proteins and are necessary to maintain the structural integrity of the contractile apparatus as well as cardiac myocyte growth and survival. We found that early induction of eccentric hypertrophy in response to volume overload (VO) stress induced impaired FA signaling associated with enhanced interstitial collagen degradation and myocyte apoptosis. These changes were markedly reduced when animals were treated with b1-AR blockers. Certain aspects of b1-AR signaling in-vivo including FA signaling downregulation, cytoskeletal rearrangement, and myocyte apoptosis could be recapitulated in-vitro using neonatal rat cardiomyocytes (NRCMs) stimulated with b1-AR agonists. Restoration of FA signaling was sufficient to block b1-AR-induced myocyte apoptosis. This led to the hypothesis that b1- AR stimulation in response to acute VO stress promotes cardiac myocyte apoptosis through alteration of FA signaling. Aim 1 will determine the molecular mechanisms involved in FA signaling downregulation induced by sustained stimulation of b1-AR in NRCMs. Aim 2 will identify the signaling pathways downstream from FA complexes that lead to the activation of initiator caspases during b1-AR-induced myocyte apoptosis. Finally, aim 3 will determine whether b1-AR-induced alteration of FA signaling is involved in myocyte apoptosis and cardiac remodeling in response to hemodynamic stress of VO. The proposed study will integrate the novel role of FA signaling in b1-AR-induced myocyte contractile dysfunction and apoptosis that may contribute to deleterious cardiac remodeling during VO-induced HF. Understanding how these approaches achieve their effects will ultimately provide a greatest impetus for developing novel therapies for human HF. PUBLIC HEALTH RELEVANCE Beta-adrenergic receptors play a central role in the neurohumoral regulation of the heart and the progression of heart failure. The proposed study will integrate the novel role of focal adhesion signaling in beta-adrenergic receptor-induced myocyte contractile dysfunction and myocyte apoptosis that may lead to heart failure. Understanding how these approaches achieve their effects will provide a greatest impetus for developing novel therapies for human heart failure.