An increase in sympathetic activity is a central feature in patients with heart failure. Cardiac myocyte loss due to apoptosis has been proposed to play an important role in the progression of heart failure. We have shown that norepinephrine, acting via the f3-adrenergic receptor (p3-AR), stimulates apoptosis in adult rat ventricular myocytes (ARVM), and the stimulation of Beta-AR and inhibitory G-protein (Gi) protects against B1-AR-stimulated apoptosis. We have also shown that Beta-AR activates mitogen-activated protein kinase (MAPKs) superfamily (which includes p38, JNKs and ERKI/2), and Gi-mediated activation of p38 protects against Beta-AR-stimulated apoptosis. Others have provided evidence that the G-protein coupled receptors (GPCR) stimulate focal adhesion assembly via the activation of small GTP-binding proteins (RhoA, racl and cdc42), thereby activating MAPKs. Small GTP-binding proteins activate focal adhesion complex proteins by actin polymerization and integrin clustering. Our recent preliminary data suggest that stimulation of beta1 integrin signaling and RhoA protects ARVM against beta-AR-stimulated apoptosis. Focal adhesion kinase (FAK), an important kinase of focal adhesion complex, is activated upon Beta-AR stimulation and inhibition of Src kinase, another enzyme of focal adhesion complex, increases beta-AR-stimulated apoptosis. These observations have led to our hypothesis that the activation of Beta1 integrin and small GTP-binding proteins, acting via common signaling pathways involving focal adhesion proteins, plays a protective role in beta-AR-stimulated apoptosis and myocardial remodeling. To test this hypothesis, we will use heterozygous knockout mice for Beta1 integrin and ARVM infection using adenoviruses.
Aim 1 will determine in vivo the role of Beta1 integrin in beta-AR-stimulated apoptosis and myocardial remodeling using heterozygous Beta1 integrin knock-out mice.
Aim 2 will define the mechanism by which beta1 integrin signaling provides protection against beta-AR-stimulated apoptosis.
Aims 3 and 4 will define the role of small GTP-binding proteins (RhoA and RacI) in beta-AR-stimulated apoptosis and signaling.
Aim 5 will determine the role of Gi proteins and identify the Gi subtypes involved in the activation of small GTP-binding proteins and FAK. These studies will advance our understanding of the signaling pathways activated by stimulation of beta-AR and Beta1 integrin, and their role in the regulation of cardiac myocyte apoptosis and myocardial remodeling.
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