G1 cyclins are involved in the mechanism of cardiac myocyte hypertrophy induced by angiotensin II.
The importance of the cell cycle in proliferating cells is well known, but little is known about the role of cell cycle regulatory proteins in cardiac myocytes, which are fully differentiated cells. The present study determined, in vitro, the effect of angiotensin II (Ang II) treatment of neonatal rat cardiac myocytes on protein levels of cyclins and retinoblastoma gene product (pRb) phosphorylation. The role of G1 cyclin/cdk in Ang II-induced cardiac myocyte hypertrophy by overexpressing cdk inhibitor p21Cip1/Waf1 or p16INK4a was also examined using recombinant adenoviral vectors encoding these genes. Western blot analysis revealed that Ang II stimulated cyclin D1, D2, D3 and A protein levels in cardiac myocytes. Moreover, Ang II phosphorylated pRb on serine 780, which is known to occur in mitotic cells during cell cycle progression. Cultured cardiac myocytes treated with Ang II and infected with either control or recombinant adenovirus indicated that expression of p21 and p16 inhibited Ang II-induced cardiac myocyte hypertrophy, [3H]leucine incorporation into total cellular proteins, and skeletal alpha-actin (SK-A) and atrial natriuretic peptide (ANP) mRNA accumulation. Control virus had no effects on these parameters. These results suggest that G1 cyclins play an important role in cardiac myocyte hypertrophy stimulated by Ang II.
Nozato
T
T
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Ito
H
H
Tamamori
M
M
Adachi
S
S
Abe
S
S
Marumo
F
F
Hiroe
M
M
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects; D056746:Cyclin G; D056766:Cyclin G1; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054462:p21-Activated Kinases
C534704:Ccng1 protein, rat; C493958:Cdkn1a protein, rat; D018797:Cell Cycle Proteins; D056746:Cyclin G; D056766:Cyclin G1; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016160:Retinoblastoma Protein; D000804:Angiotensin II; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D018844:Cyclin-Dependent Kinases