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(Circulation Research. 2009;104:1347.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Positive Transcription Elongation Factor b Activity in Compensatory Myocardial Hypertrophy is Regulated by Cardiac Lineage Protein-1

Jorge Espinoza-Derout, Michael Wagner, Louis Salciccioli, Jason M. Lazar, Sikha Bhaduri, Eduardo Mascareno, Brahim Chaqour, M.A.Q. Siddiqui

From the Department of Anatomy and Cell Biology (J.E.-D., M.W., S.B., E.M., B.C., M.A.Q.S.), Center for Cardiovascular and Muscle Research; and Division of Cardiology (L.S., J.M.L.), State University of New York Downstate Medical Center, Brooklyn.

Correspondence to M.A.Q. Siddiqui, Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203. E-mail maq.siddiqui{at}downstate.edu

Emerging evidence illustrates the importance of the positive transcription elongation factor (P-TEF)b in control of global RNA synthesis, which constitutes a major feature of the compensatory response to diverse hypertrophic stimuli in cardiomyocytes. P-TEFb complex, composed of cyclin T and cdk9, is critical for elongation of nascent RNA chains via phosphorylation of the carboxyl-terminal domain of RNA polymerase (Pol) II. We and others have shown that the activity of P-TEFb is inhibited by its association with cardiac lineage protein (CLP)-1, the mouse homolog of human HEXIM1, in various physiological and pathological conditions. To investigate the mechanism of control of P-TEFb activity by CLP-1 in cardiac hypertrophy, we used a transgenic mouse model of hypertrophy caused by overexpression of calcineurin in the heart. We observed that the level of CLP-1 associated with P-TEFb was reduced markedly in hypertrophic hearts. We also generated bigenic mice (MHC–cyclin T1/CLP-1^+/–) by crossing MHC–cyclin T1 transgenic mice with CLP-1 heterozygote. The bigenic mice exhibit enhanced susceptibility to hypertrophy that is accompanied with an increase in cdk9 activity via an increase in serine 2 phosphorylation of carboxyl-terminal domain and an increase in GLUT1/GLUT4 ratio. These mice have compensated systolic function without evidence of fibrosis and reduced lifespan. These data suggest that the reduced level of CLP-1 introduced in the background of elevated levels of cyclin T1 elevates derepression of P-TEFb activity and emphasizes the importance of the role of CLP-1 in the mechanism governing compensatory hypertrophy in cardiomyocytes.

Key Words: myocardial hypertrophy • transcriptional elongation • CLP-1 • HEXIM1

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