Cardiac sarcomeric function, small G-protein signaling, and heart failure.
Molecular signaling that induces cardiac hypertrophy and dilated cardiomyopathy and the transition to decompensation is complex and poorly understood. Extrinsic hemodynamic stresses such as hypertension as well as intrinsic stresses such as genetic defects in sarcomeric proteins and cytoskeletal proteins trigger the process. Both stresses lead to similar outcomes of altered contractility and eventually heart failure. Activation of G-protein coupled receptors initiates cascades of signaling pathways, which promote cardiac hypertrophy by phosphorylation of transcriptional factors and changes in gene expression. Stimulation of these signaling molecules also activates a variety of kinases and phosphatases that induce altered phosphorylation of myofilament proteins. In this review, we focused on these functional effects of small G-protein, Ras and Rho, signaling pathways that reside within the cytoplasm downstream of membrane receptors and upstream of the transcriptional factors. It has been demonstrated that phosphorylation of myofilament proteins alter mechano-energetics of myofilament and contractile function of the heart. Therefore, understanding the role of low molecular weight G-proteins in both cardiac and vascular biology has become particularly important in view of the development of specific inhibitors of effectors of small G-proteins such as p38 MAP kinase and Rho-dependent kinase.
Vahebi
S
S
Department of Physiology and Biophysics, Center for Cardiovascular Research College of Medicine, University of Illinois, Chicago, IL 60612-7342, USA.
Solaro
R J
RJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology*; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D012518:Sarcomeres / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000502:physiology
C515907:PAK2 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D020559:Monomeric GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D002118:Calcium