Protein kinase C in angiotensin II signalling in neonatal rat cardiac fibroblasts. Role in the mitogenic response.
The mitogenic effects of angiotensin II on cardiac fibroblasts are mediated by membrane receptors that are classified as AT1. These receptors are prototypical of the seven transmembrane group of receptors that couple, via G-proteins, to phospholipase C, thereby generating the endogenous activator of protein kinase C, diacylglycerol. Phorbol ester activators of protein kinase C exhibit growth-promoting effects in many cell types, suggesting that this enzyme may be responsible for the growth effects of angiotensin II on cardiac fibroblasts. Both kinase assays and Western analysis demonstrated that angiotensin II does induce translocation of protein kinase C to the detergent-soluble, membrane compartment of cardiac fibroblasts. Although translocation is commonly interpreted to mean activation of protein kinase C, in situ assays on permeabilized cells failed to detect increased enzymatic activity in response to angiotensin II. Nonetheless, this hormone did activate protein kinase C, leading to activation of mitogen-activated protein (MAP) kinases. However, a PKC-independent pathway for activation of MAP kinases exists as well. Downregulation and inhibitor studies indicated that protein kinase C is not critically involved in angiotensin II-induced thymidine incorporation into DNA. Furthermore, phorbol esters that activate protein kinase C do not elicit a mitogenic response in these cells. In conclusion, the mitogenic effects of angiotensin II on cardiac fibroblasts are not simply explained by activation of protein kinase C.
Booz
G W
GW
Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822, USA.
Baker
K M
KM
D000470:Alkaloids; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D053119:Benzophenanthridines; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011945:Receptors, Angiotensin / Q000502:physiology; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism
D000470:Alkaloids; D053119:Benzophenanthridines; D010617:Phenanthridines; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D004247:DNA; C016299:chelerythrine; D011493:Protein Kinase C; D013936:Thymidine