NOVEL SIGNALING PATHWAYS FOR ANGIOTENSIN II IN THE HEART

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DESCRIPTION (Adapted from Investigator's Abstract): Angiotensin II, the effector peptide of the renin-angiotensin system, regulates volume and electrolyte homeostasis and is involved in cardiac and vascular cellular growth in humans and other species. This system, which has been conserved throughout evolution, plays an important role in cardiac and vascular pathology associated with hypertension, coronary heart disease, myocarditis and congestive heart failure. These critical actions of angiotensin II are mediated primarily through the AT1, G-protein (guanylyl nucleotide binding protein) coupled receptor. In addition to coupling to conventional G-protein signal transduction pathways, the AT1 receptor was recently shown to increase the tyrosine phosphorylation of several intracellular substrates, including the STAT (Signal Transducers and Activators of Transcription) family of novel transcription factors, in rat cardiac fibroblasts, myocytes and vascular smooth muscle cells, and AT1A receptor transfected Chinese Hamster Ovary (CHO) cells. It is likely that this pathway has a role in angiotensin II mediated gene regulation, cardiac and vascular cellular growth and inflammatory responses. The AT1 receptor, which lacks intrinsic tyrosine kinase activity, has been shown in rat vascular smooth muscle cells and cardiomyocytes, to associate with Jak2, a member of the Janus family of kinases (JAK), implicated in the tyrosine phosphorylation of the STATs. These findings, as originally described for cytokines (interleukins and interferon gamma), suggest that the AT1 receptor may contain a docking site for Jak2. Analysis of the amino acid sequence of the AT1 receptor, also suggests potential binding motifs for Src kinase, Stat3, and SH-PTP1D (a tyrosine phosphatase), all of which are components of the JAK-STAT pathway. However, for G-protein receptors, the proximal mechanisms for coupling and activation of these novel signal transduction pathways, remain to be elucidated. Utilizing molecular, biochemical and cellular approaches, the PI will determine the structural regions of the AT1 receptor responsible for the interaction of signaling proteins and cytosolic tyrosine kinases and define the role of G-proteins in the recruitment and activation of the JAK-STAT components. These studies are important for elucidating angiotensin II mediated actions in target cells and for a more complete understanding of the molecular signaling of the heptahelical superfamily of receptors.