The renin-angiotensin system is a major regulator of fluid and volume homeostasis in mammalian species. In pathological processes such as hypertension and congestive heart failure, inhibition of angiotensin converting enzyme results in decreased levels of angiotensin II and provides beneficial clinical effects. Human studies, in which the angiotensin II receptor antagonist, saralasin, was used to decrease vascular resistance, showed reduction in cardiac output indicating that angiotensin II may be an in vivo modulator of cardiac contractile function. In cardiac tissue angiotensin II participates in the regulation of transmembrane signalling and cardiac muscle cell growth. The cardiac effects of angiotensin II could be mediated by circulating peptide produced by the peripheral renin-angiotensin system or a locally active system in the heart. Identification of the precursor genes for the renin angiotensin system in the heart and quantifiable production of translatable product (angiotensin II) suggests that mechanical and humoral regulation of a localized renin angiotensin system could have significant implications for angiotensin II-mediated responses in cardiac tissue. Inhibition of the angiotensin II-mediated hypertrophic response in neonatal rat cardiomyocytes by the protein kinase C inhibitor, staurosporin, suggests that angiotensin II stimulated increases in second messengers may be integrally involved in cardiac growth processes. We propose to determine if the angiotensin II-stimulated increases in cytosolic free Ca2+, inositol phosphates, and diacylglycerol-protein kinase C are mediated by one or multiple membrane receptors, and to characterize the time course for these responses. The putative guanine nucleotide binding proteins that couple angiotensin II receptors to effector responses will be determined using pharmacologic manipulation with cholera and pertussis toxins. We have hypothesized that protein kinase C is involved in mediating the cardiac hypertrophic growth response to angiotensin II. We will determine the subcellular distribution of specific protein kinase C isozymes and their regulation in nuclear and cytoskeletal fractions by angiotensin II and phorbol esters. These studies will provide a more complete understanding of the role of angiotensin peptides in the modulation of cardiac function at the level of second messengers.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044379-02
Application #
3363103
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1991-08-08
Project End
1994-07-31
Budget Start
1992-08-28
Budget End
1993-07-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Weis Center for Research-Geisinger Clinc
Department
Type
DUNS #
079161360
City
Danville
State
PA
Country
United States
Zip Code
17822
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Dostal, D E; Booz, G W; Baker, K M (2000) Regulation of angiotensinogen gene expression and protein in neonatal rat cardiac fibroblasts by glucocorticoid and beta-adrenergic stimulation. Basic Res Cardiol 95:485-90
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Thomas, W G; Thekkumkara, T J; Motel, T J et al. (1995) Stable expression of a truncated AT1A receptor in CHO-K1 cells. The carboxyl-terminal region directs agonist-induced internalization but not receptor signaling or desensitization. J Biol Chem 270:207-13
Lin, C; Baker, K M; Thekkumkara, T J et al. (1995) Sensitive bioassay for the detection and quantification of angiotensin II in tissue culture medium. Biotechniques 18:1014-20
Booz, G W; Baker, K M (1995) Protein kinase C in angiotensin II signalling in neonatal rat cardiac fibroblasts. Role in the mitogenic response. Ann N Y Acad Sci 752:158-67
Schorb, W; Conrad, K M; Singer, H A et al. (1995) Angiotensin II is a potent stimulator of MAP-kinase activity in neonatal rat cardiac fibroblasts. J Mol Cell Cardiol 27:1151-60

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