Essential roles for G1 cyclin-dependent kinase activity in development of cardiomyocyte hypertrophy.

Although cardiomyocytes undergo terminal differentiation soon after birth, irreversibly withdrawing from the cell cycle, growth stimulation induces cell hypertrophy. Such growth stimulation is also responsible for the upregulation of G1 cyclins and cyclin-dependent kinase (CDK) activity in proliferating cells. We sought to determine whether G1 CDK activity is involved in the hypertrophy of rat neonatal cardiomyocytes in culture. We show that serum stimulation promoted the G1 CDK activity without induction of DNA synthesis in cardiomyocytes. Furthermore, overexpression of CDK inhibitors p16(INK4a) and p21(CIP1/WAF1) by use of the adenovirus vector effectively prevented cell enlargement and depressed serum-induced protein synthesis and expression of skeletal alpha-actin and atrial natriuretic factor, genetic markers of cardiac hypertrophy. These results suggest that the G1 CDK activity promoted by serum stimulation is required for the induction of cardiomyocyte hypertrophy and provide novel evidence for understanding the regulation of cardiac hypertrophy by cell cycle regulators.

[1]  H. Ito,et al.  Endothelins and cardiac hypertrophy. , 1997, Life sciences.

[2]  JunichiSadoshima,et al.  Angiotensin II and Serum Differentially Regulate Expression of Cyclins, Activity of Cyclin-Dependent Kinases, and Phosphorylation of Retinoblastoma Gene Product in Neonatal Cardiac Myocytes , 1997 .

[3]  J. Sadoshima,et al.  The cellular and molecular response of cardiac myocytes to mechanical stress. , 1997, Annual review of physiology.

[4]  F. Marumo,et al.  Overexpression of cell cycle inhibitors (p16INK4 and p21Cip1) and cyclin D1 using adenovirus vectors regulates proliferation of rat mesangial cells. , 1997, Journal of the American Society of Nephrology : JASN.

[5]  C. Sherr.  Cancer Cell Cycles , 1996, Science.

[6]  H. Hirai,et al.  Interaction of D-type cyclins with a novel myb-like transcription factor, DMP1 , 1996, Molecular and cellular biology.

[7]  M. Abdellatif,et al.  Human E2F-1 reactivates cell cycle progression in ventricular myocytes and represses cardiac gene transcription. , 1996, Developmental biology.

[8]  Y. Kanegae,et al.  Efficient generation of recombinant adenoviruses using adenovirus DNA-terminal protein complex and a cosmid bearing the full-length virus genome. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[9]  C. Marshall,et al.  Hypertrophic Agonists Stimulate the Activities of the Protein Kinases c-Raf and A-Raf in Cultured Ventricular Myocytes (*) , 1995, The Journal of Biological Chemistry.

[10]  Meihong Lin,et al.  Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression. , 1995, The Journal of clinical investigation.

[11]  James M. Roberts,et al.  Inhibitors of mammalian G1 cyclin-dependent kinases. , 1995, Genes & development.

[12]  R. Weinberg,et al.  The retinoblastoma protein and cell cycle control , 1995, Cell.

[13]  L. Kirshenbaum,et al.  Adenovirus E1A Represses Cardiac Gene Transcription and Reactivates DNA Synthesis in Ventricular Myocytes, via Alternative Pocket Protein- and p300-binding Domains (*) , 1995, The Journal of Biological Chemistry.

[14]  F. Marumo,et al.  Distribution of mRNAs for natriuretic peptides in RV hypertrophy after pulmonary arterial banding. , 1995, The American journal of physiology.

[15]  K. Giacomini,et al.  Increased 1,4-dihydropyridine binding sites in serum-stimulated cardiomyocyte hypertrophy. , 1994, The Journal of pharmacology and experimental therapeutics.

[16]  S. Shurtleff,et al.  D-type cyclin-dependent kinase activity in mammalian cells , 1994, Molecular and cellular biology.

[17]  M. Shichiri,et al.  Insulinlike Growth Factor‐I Induces Hypertrophy With Enhanced Expression of Muscle Specific Genes in Cultured Rat Cardiomyocytes , 1993, Circulation.

[18]  J. Nevins,et al.  E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. , 1992, Science.

[19]  Y. Hirata,et al.  Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. , 1991, Circulation research.

[20]  T. Parker,et al.  Cardiac Myocytes as Targets for the Action of Peptide Growth Factors , 1990, Circulation.

[21]  K. Baker,et al.  [Sar1]angiotensin II receptor-mediated stimulation of protein synthesis in chick heart cells. , 1990, The American journal of physiology.

[22]  T. Parker,et al.  Peptide growth factors can provoke "fetal" contractile protein gene expression in rat cardiac myocytes. , 1990, The Journal of clinical investigation.

[23]  P. Simpson.  Proto-oncogenes and cardiac hypertrophy. , 1989, Annual review of physiology.

[24]  K. Chien,et al.  Terminally differentiated neonatal rat myocardial cells proliferate and maintain specific differentiated functions following expression of SV40 large T antigen. , 1988, The Journal of biological chemistry.

[25]  R. Roberts,et al.  Differentiation of cardiac myocytes after mitogen withdrawal exhibits three sequential states of the ventricular growth response , 1988, The Journal of cell biology.

[26]  R. Zak.  Development and Proliferative Capacity of Cardiac Muscle Cells , 1974, Circulation research.