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

描述（由申请人提供）：在心脏中，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，可以增强心肌对应激或运动的反应。然而，b- AR的持续激活会损害心肌细胞的收缩能力并诱导心肌细胞凋亡，从而导致心力衰竭（HF）。尽管人们普遍认为细胞收缩功能障碍和b- ar诱导的HF是相互关联的，但其中的分子机制仍然知之甚少。整合素和局灶黏附（FA）都是连接细胞外基质（ECM）与细胞骨架蛋白的附着位点，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要的。我们发现，容量过载（VO）应激引起的早期偏心肥大诱导了与间质胶原降解和心肌细胞凋亡增强相关的FA信号受损。当动物接受b1-AR阻滞剂治疗时，这些变化明显减少。体内b1-AR信号的某些方面，包括FA信号下调、细胞骨架重排和肌细胞凋亡，可以在体外用b1-AR激动剂刺激新生大鼠心肌细胞（NRCMs）来重现。FA信号的恢复足以阻断b1- ar诱导的心肌细胞凋亡。这导致假设b1- AR刺激响应急性VO应激通过改变FA信号促进心肌细胞凋亡。目的1将确定nrcm中b1-AR持续刺激诱导FA信号下调的分子机制。目的2将确定b1- ar诱导的心肌细胞凋亡过程中，FA复合物下游导致启动物半胱天蛋白酶激活的信号通路。最后，目的3将确定b1- ar诱导的FA信号的改变是否参与心肌细胞凋亡和心脏重塑，以响应VO的血流动力学应激。该研究将整合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，这可能有助于vo诱导的心衰期间有害的心脏重塑。了解这些方法如何达到其效果将最终为开发人类心衰的新疗法提供最大的动力。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。该研究将整合局灶黏附信号在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可能导致心力衰竭的新作用。了解这些方法如何达到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.