This is an application on the inhibition of cell proliferation induced by atriopeptins (APs) and nitric oxide (NO)-generating drugs.
The aims are based on our observations that APs and NO-generating vasodilators inhibit serum-induced mitogenesis and proliferation of cultured rat aortic smooth muscle and renal mesangial cells and that 8-bromo-cGMP mimics these effects. These results support the existence of a novel function for a vasoactive hormone: atrial natriuretic hormone and a local regulator of vascular tone: endothelium derived nitric oxide (EDNO). The following specific aims form the basis of the proposed experiments:
Aim 1 : To compare the antimitogenic effects of APs, NO-generating vasodilators and 8- bromo-cGMP, in primary versus subcultured aortic smooth muscle and mesangial cells, and in cell types other than aortic smooth muscle and mesangial cells; we propose to use cultured smooth muscle cells from coronary artery, aortic endothelial cells, renal epithelial cells nad 3T3 fibroblasts.
Aim 2 : To identify the cell cycle phase that is affected by APs, NO-generating agents and 8-bromo-cGMP and to investigate the effects of these antimitogens on thymidine uptake a sa possible mechanism of action.
Aim 3 : To investigate the effects of APs, NO-generating vasodilators and 8-bromo-cGMP on mitogenesis nad cell proliferation induced by defined growth factors that affect early or late events in the G1 period of the cell cycle; early-acting mitogens that will be tested include, platelet-derived growth factor, basic fibroblast growth factor and epidermal growth factor whereas a later-acting mitogen that will be tested is insulin-like growth factor I (somatomedin C).
Aim 4 : To investigate the effects of APs, NO-generating vasodilators and 8-bromo-cGMP on various biochemical events induced by growth factors; these include the modulation of the increase of cytosolic free Ca2+, cell pH, accumulation of inositol phosphates and diglycerides, and expression of proto-oncogene, c-fos.
Aim 5 : To evaluate the short-term and long-term effects of the aforementioned antimitogens on receptor binding, affinity and number of receptor for growth factors.
Aim 6 : To investigate whether the antimitogenic and antiproliferative effects of APs nad NO-generating vasodilators are mediated by cGMP only, or whether cGMP-independent mechanisms also contribute.
Aim 7 : To establish whether EDNO/ endothelium-derived relaxing factor (EDRF) inhibits vascular smooth muscle/mesangial cell mitogenesis and proliferation, in cocultures of endothelial and vascular smooth muscle/mesangial cells. The results will provide information on the role and mechanism of action of EDRF/NO, atrial natriuretic peptides and cyclic GMP in the regulation of vascular smooth muscle and mesangial cell mitogenesis and proliferation in vitro. These experiments may promote the concept that EDRF/EDNO and atrial natriuretic hormone play an important role in maintaining the mitogenic quiescence of vascular smooth muscle and renal mesangial cells.

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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University of Tennessee Health Science Center
Schools of Medicine
United States
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Brown, C; Lin, Y; Hassid, A (2001) Requirement of protein tyrosine phosphatase SHP2 for NO-stimulated vascular smooth muscle cell motility. Am J Physiol Heart Circ Physiol 281:H1598-605
Brown, C; Pan, X; Hassid, A (1999) Nitric oxide and C-type atrial natriuretic peptide stimulate primary aortic smooth muscle cell migration via a cGMP-dependent mechanism: relationship to microfilament dissociation and altered cell morphology. Circ Res 84:655-67
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