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

Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203, USA.
Circulation Research (Impact Factor: 11.02). 06/2009; 104(12):1347-54. DOI: 10.1161/CIRCRESAHA.108.191726
Source: PubMed


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.

Download full-text


Available from: Eduardo Mascareno, Jun 05, 2014
  • Source
    • "HEXIM1 knockout mice exhibited LV hypertrophy during the late stages of fetal development, whereas heart-specific activation of P-TEFb provoked LV hypertrophy in mice [13] [14]. The genetic reduction of HEXIM1 in the background of elevated levels of CycT1 derepresses P-TEFb activity, emphasizing the importance of the role of HEXIM1 in the mechanism governing cardiac hypertrophy [15]. Recently, we also revealed that HEXIM1 suppressed endothelin-1 (ET-1)- induced myocyte growth and RV hypertrophy in hypoxia-induced PH model mice [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary hypertension (PH) sustains elevation of pulmonary vascular resistance and ultimately leads to right ventricular (RV) hypertrophy and failure and death. Recently, proangiogenic factors hypoxia-inducible factor-1 alpha (HIF-1a) and vascular endothelial growth factor (VEGF) have been known to promote left ventricular myocardial angiogenesis and lead to cardiac hypertrophy, and this would be involved in RV hypertrophy of PH patients. Previously, we revealed that overexpression of HEXIM1 prevents endothelin-1-induced cardiomyocyte hypertrophy and hypertrophic genes expression, and that cardiomyocyte-specific HEXIM1 transgenic mice ameliorates RV hypertrophy in hypoxia-induced PH model. Given these results, here we analyzed the effect of HEXIM1 on the expression of HIF-1α and VEGF and on myocardial angiogenesis of RV in PH. We revealed that overexpression of HEXIM1 prevented hypoxia-induced expression of HIF-1α protein and its target genes including VEGF in the cultured cardiac myocytes and fibroblasts, and that cardiomyocyte-specific HEXIM1 transgenic mice repressed RV myocardial angiogenesis in hypoxia-induced PH model. Thus, we conclude that HEXIM1 could prevent RV hypertrophy, at least in part, via suppression of myocardial angiogenesis through down-regulation of HIF-1α and VEGF in the myocardium under hypoxic condition.
    Biochemical and Biophysical Research Communications 10/2014; 453(3). DOI:10.1016/j.bbrc.2014.09.135 · 2.30 Impact Factor
  • Source
    • "larly important to support transcriptional program that meets the heightened needs of energy production in the myocardium. Deregulation of transcriptional elongation has been previously implicated in pathologic cardiac hypertrophy (Anand et al., 2013; Espinoza-Derout et al., 2009; Sano et al., 2002). The link between energy metabolism and NELF raises the distinct possibility that pharmacological agents aimed at enhancing Pol II pausing may overcome stress-triggered metabolic deficiency and cardiac abnormality in humans. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Negative elongation factor (NELF) is known to enforce promoter-proximal pausing of RNA polymerase II (Pol II), a pervasive phenomenon observed across multicellular genomes. However, the physiological impact of NELF on tissue homeostasis remains unclear. Here, we show that whole-body conditional deletion of the B subunit of NELF (NELF-B) in adult mice results in cardiomyopathy and impaired response to cardiac stress. Tissue-specific knockout of NELF-B confirms its cell-autonomous function in cardiomyocytes. NELF directly supports transcription of those genes encoding rate-limiting enzymes in fatty acid oxidation (FAO) and the tricarboxylic acid (TCA) cycle. NELF also shares extensively transcriptional target genes with peroxisome proliferator-activated receptor α (PPARα), a master regulator of energy metabolism in the myocardium. Mechanistically, NELF helps stabilize the transcription initiation complex at the metabolism-related genes. Our findings strongly indicate that NELF is part of the PPARα-mediated transcription regulatory network that maintains metabolic homeostasis in cardiomyocytes.
    Cell Reports 03/2014; 7(1). DOI:10.1016/j.celrep.2014.02.028 · 8.36 Impact Factor
  • Source
    • "Siddiqui and colleagues generated two different bigenic mice (alphaMHC–cyclin T1/CLP-1+/− and alphaMHC–angiotensin II/CLP-1+/−) by crossing alpha-MHC promoter-driven cyclin T1 or angiotensin II expressing transgenic mice with CLP-1 heterozygote, respectively. These bigenic mice exhibit enhanced susceptibility to LVH that is accompanied with an increase in Cdk9 activity via an increase in Ser2 phosphorylation of CTD or with activation of angiotensin II-TGF-beta1-CLP-1-Smad3 signaling axis and natriuretic peptide expression, respectively [23], [24]. HEXIM1 has also been known to have antiangiogenic effect by preventing estrogen-induced vascular endothelial growth factor (VEGF) transcription through inhibition of estrogen receptor-alpha recruitment to the VEGF promoter in MCF-7 breast cancer cells [25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Right ventricular hypertrophy (RVH) and right ventricular (RV) contractile dysfunction are major determinants of prognosis in pulmonary arterial hypertension (PAH) and PAH remains a severe disease. Recently, direct interruption of left ventricular hypertrophy has been suggested to decrease the risk of left-sided heart failure. Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) is a negative regulator of positive transcription elongation factor b (P-TEFb), which activates RNA polymerase II (RNAPII)-dependent transcription and whose activation is strongly associated with left ventricular hypertrophy. We hypothesized that during the progression of PAH, increased P-TEFb activity might also play a role in RVH, and that HEXIM1 might have a preventive role against such process. We revealed that, in the mouse heart, HEXIM1 is highly expressed in the early postnatal period and its expression is gradually decreased, and that prostaglandin I(2), a therapeutic drug for PAH, increases HEXIM1 levels in cardiomyocytes. These results suggest that HEXIM1 might possess negative effect on cardiomyocyte growth and take part in cardiomyocyte regulation in RV. Using adenovirus-mediated gene delivery to cultured rat cardiomyocytes, we revealed that overexpression of HEXIM1 prevents endothelin-1-induced phosphorylation of RNAPII, cardiomyocyte hypertrophy, and mRNA expression of hypertrophic genes, whereas a HEXIM1 mutant lacking central basic region, which diminishes P-TEFb-suppressing activity, could not. Moreover, we created cardiomyocyte-specific HEXIM1 transgenic mice and revealed that HEXIM1 ameliorates RVH and prevents RV dilatation in hypoxia-induced PAH model. Taken together, these findings indicate that cardiomyocyte-specific overexpression of HEXIM1 inhibits progression to RVH under chronic hypoxia, most possibly via inhibition of P-TEFb-mediated enlargement of cardiomyocytes. We conclude that P-TEFb/HEXIM1-dependent transcriptional regulation may play a pathophysiological role in RVH and be a novel therapeutic target for mitigating RVH in PAH.
    PLoS ONE 12/2012; 7(12):e52522. DOI:10.1371/journal.pone.0052522 · 3.23 Impact Factor
Show more