© 1997 American Heart Association, Inc.
Articles |
Angiotensin II and Serum Differentially Regulate Expression of Cyclins, Activity of Cyclin-Dependent Kinases, and Phosphorylation of Retinoblastoma Gene Product in Neonatal Cardiac Myocytes
the Cardiovascular Research Center, Division of Cardiology, University of Michigan Medical Center, Ann Arbor.
Correspondence to Dr Seigo Izumo, Cardiovascular Research Center, University of Michigan Medical Center, Ann Arbor, MI 48109-0644. E-mail sizumo@umich.edu
The hypertrophic response in cardiac myocytes and the mitogenic response in other cell types share various early cellular responses. However, how the subsequent cell growth response, such as cell cycle machinery, is regulated in cardiac hypertrophy is not understood. Using cultured neonatal rat cardiac myocytes, we examined the effect of angiotensin II (Ang II), a hypertrophic stimulus, on mRNA and protein expression of cyclins and cyclin-dependent protein kinases (cdks), activity of cdks, and phosphorylation of retinoblastoma gene product (pRb). The effect of FCS, a stimulus that was previously reported to initiate both protein and DNA synthesis in cardiac myocytes, was also examined for comparison. Ang II activated cdk4 and caused phosphorylation of pRb, peaking at 12 hours, but subsequently downregulated cyclin D1, D3, and A expression and cdk2 activity. FCS increased the expression of G1-S cyclins, caused activation of cdk4, cdk2, and cdc2, and strongly phosphorylated pRb but failed to significantly stimulate DNA synthesis in neonatal cardiac myocytes. These results suggest that Ang II transiently activates but subsequently downregulates cell cycle regulators. Induction of G1 and G1-S cyclins and activation of cdks by FCS are not sufficient to drive cardiac myocytes into S phase. The functional role of pRb phosphorylation by Ang II and serum stimulation and, by inference, the subsequent liberation of E2F in terminally differentiated myocytes remain to be elucidated.
Key Words: cell cycle • hypertrophy • angiotensin II • cardiac myocyte • retinoblastoma gene product
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