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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Renal Study Section (CVB)
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Buxton, Denis B
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East Tennessee State University
Schools of Medicine
Johnson City
United States
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Foster, Cerrone R; Singh, Mahipal; Subramanian, Venkateswaran et al. (2011) Ataxia telangiectasia mutated kinase plays a protective role in ?-adrenergic receptor-stimulated cardiac myocyte apoptosis and myocardial remodeling. Mol Cell Biochem 353:13-22
Singh, Mahipal; Roginskaya, Marina; Dalal, Suman et al. (2010) Extracellular ubiquitin inhibits beta-AR-stimulated apoptosis in cardiac myocytes: role of GSK-3beta and mitochondrial pathways. Cardiovasc Res 86:20-8
Krishnamurthy, Prasanna; Peterson, J Thomas; Subramanian, Venkateswaran et al. (2009) Inhibition of matrix metalloproteinases improves left ventricular function in mice lacking osteopontin after myocardial infarction. Mol Cell Biochem 322:53-62
Mountain, Deidra J H; Singh, Mahipal; Singh, Krishna (2008) Interleukin-1beta-mediated inhibition of the processes of angiogenesis in cardiac microvascular endothelial cells. Life Sci 82:1224-30
Menon, Bindu; Johnson, Jennifer N; Ross, Robert S et al. (2007) Glycogen synthase kinase-3beta plays a pro-apoptotic role in beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes: Role of beta1 integrins. J Mol Cell Cardiol 42:653-61
Mountain, Deidra J H; Singh, Mahipal; Menon, Bindu et al. (2007) Interleukin-1beta increases expression and activity of matrix metalloproteinase-2 in cardiac microvascular endothelial cells: role of PKCalpha/beta1 and MAPKs. Am J Physiol Cell Physiol 292:C867-75
Singh, Mahipal; Ananthula, Srinivas; Milhorn, Denise M et al. (2007) Osteopontin: a novel inflammatory mediator of cardiovascular disease. Front Biosci 12:214-21
Zhao, Xue; Johnson, Jennifer N; Singh, Krishna et al. (2007) Impairment of myocardial angiogenic response in the absence of osteopontin. Microcirculation 14:233-40
Krishnamurthy, Prasanna; Subramanian, Venkateswaran; Singh, Mahipal et al. (2007) Beta1 integrins modulate beta-adrenergic receptor-stimulated cardiac myocyte apoptosis and myocardial remodeling. Hypertension 49:865-72
Subramanian, Venkateswaran; Krishnamurthy, Prasanna; Singh, Krishna et al. (2007) Lack of osteopontin improves cardiac function in streptozotocin-induced diabetic mice. Am J Physiol Heart Circ Physiol 292:H673-83

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