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.
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