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.
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.
