Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression

Abstract

Accumulating evidence suggests that angiotensin II type II (AT 2 ) receptor subtype negatively regulates cell proliferation in pathophysiological conditions associated with tissue remodeling. However, the mechanisms through which AT 2 receptor achieves this effect remain poorly understood. In this study, we demonstrate that expression of AT 2 receptor inhibits the proliferation of rat fibroblasts in a ligand-independent manner. The antiproliferative action of AT 2 is dependent on the density of surface receptors. We show that AT 2 receptor expression negatively regulates G1 phase progression in both cycling cells and G0-arrested cells stimulated to re-enter the cell cycle, but has no detectable effect on apoptosis. The delay in cell-cycle progression of AT 2 -expressing cells is associated with downregulation of cyclin E expression, decreased assembly of cyclin E-Cdk2 complexes, and the resulting attenuation of Cdk2 activation. The induction of Cdk4 expression and activity is also markedly attenuated, which likely contributes to the inhibition of cyclin E expression. Ectopic expression of Cdk4 alleviates the proliferation defect of AT 2 -expressing cells. These findings suggest that the growth-inhibitory effects of the AT 2 receptor are attributable in part to its spontaneous inhibitory action on the cell cycle machinery.

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…The AT 2 receptor has been implicated in cardiovascular disease as a beneficial moiety due to its proposed vasodilatory role, ability to inhibit cell growth, induce apoptosis, and inhibit activation of MAPK functions that, overall, appear to counterbalance the actions of the AT 1 receptor (Berk, 2003;Miura et al, 2010). Overall, the AT 2 receptor may play a role in several AT 1 receptor-independent biologic processes (Mifune et al, 2000;Ruiz-Ortega et al, 2000Zhu et al, 2000;Weidekamm et al, 2002;Benndorf et al, 2003;Gingras et al, 2003;Caballero et al, 2004;Zhao et al, 2005b;Mertens et al, 2010). Furthermore, activation of the AT 2 receptor inhibits autophagy mediated by the AT 1 receptor in cardiomyocytes (Porrello et al, 2009).…”

“…Activation of the AT 2 receptor inhibits autophagy mediated by the AT 1 receptor in cardiomyocytes (Porrello et al, 2009). Overall, the AT 2 receptor may play a role in several AT 1 receptor-independent biologic processes as well (RuizOrtega et al, 2000(RuizOrtega et al, , 2001aMifune et al, 2000;Weidekamm et al, 2002;Benndorf et al, 2003;Gingras et al, 2003;Caballero et al, 2004;Zhao et al, 2005b;Zhu et al, 2000;Mertens et al, 2010). Notably, activation of the AT 2 receptor in cells of neuronal origin, induced neurite outgrowth, and elongation mediated cellular excitability and migration and, in some cases, caused neuronal cell death (Guimond and Gallo-Payet, 2012).…”

Angiotensin II and Cell Cycle Regulation

“…49 CKI expression was not influenced in the AT 2 -receptors expressing fibroblasts. 49 Ang II has antiproliferative effects without causing apoptosis in PC12 cells, a pheochromocytoma cell line that exclusively express AT 2 -receptors. 50 Antiproliferative effects of Ang II in PC12 cells are not associated with apoptosis, but represent a differentiation process.…”

“…48 Overexpression of AT 2 -receptors in fibroblasts had antiproliferative effects without causing apoptosis. 49 This effect was associated with an inhibition of CDK4 and cyclin E expression. 49 CKI expression was not influenced in the AT 2 -receptors expressing fibroblasts.…”

“…49 This effect was associated with an inhibition of CDK4 and cyclin E expression. 49 CKI expression was not influenced in the AT 2 -receptors expressing fibroblasts. 49 Ang II has antiproliferative effects without causing apoptosis in PC12 cells, a pheochromocytoma cell line that exclusively express AT 2 -receptors.…”