Document Detail


Cardiac lineage protein-1 (CLP-1) regulates cardiac remodeling via transcriptional modulation of diverse hypertrophic and fibrotic responses and angiotensin II-transforming growth factor β (TGF-β1) signaling axis.
MedLine Citation:
PMID:  22308025     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
It is well known that the renin-angiotensin system contributes to left ventricular hypertrophy and fibrosis, a major determinant of myocardial stiffness. TGF-β1 and renin-angiotensin system signaling alters the fibroblast phenotype by promoting its differentiation into morphologically distinct pathological myofibroblasts, which potentiates collagen synthesis and fibrosis and causes enhanced extracellular matrix deposition. However, the atrial natriuretic peptide, which is induced during left ventricular hypertrophy, plays an anti-fibrogenic and anti-hypertrophic role by blocking, among others, the TGF-β-induced nuclear localization of Smads. It is not clear how the hypertrophic and fibrotic responses are transcriptionally regulated. CLP-1, the mouse homolog of human hexamethylene bis-acetamide inducible-1 (HEXIM-1), regulates the pTEFb activity via direct association with pTEFb causing inhibition of the Cdk9-mediated serine 2 phosphorylation in the carboxyl-terminal domain of RNA polymerase II. It was recently reported that the serine kinase activity of Cdk9 not only targets RNA polymerase II but also the conserved serine residues of the polylinker region in Smad3, suggesting that CLP-1-mediated changes in pTEFb activity may trigger Cdk9-dependent Smad3 signaling that can modulate collagen expression and fibrosis. In this study, we evaluated the role of CLP-1 in vivo in induction of left ventricular hypertrophy in angiotensinogen-overexpressing transgenic mice harboring CLP-1 heterozygosity. We observed that introduction of CLP-1 haplodeficiency in the transgenic α-myosin heavy chain-angiotensinogen mice causes prominent changes in hypertrophic and fibrotic responses accompanied by augmentation of Smad3/Stat3 signaling. Together, our findings underscore the critical role of CLP-1 in remodeling of the genetic response during hypertrophy and fibrosis.
Authors:
Eduardo Mascareno; Josephine Galatioto; Inna Rozenberg; Louis Salciccioli; Haroon Kamran; Jason M Lazar; Fang Liu; Thierry Pedrazzini; M A Q Siddiqui
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-02-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-04-16     Completed Date:  2012-06-19     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13084-93     Citation Subset:  IM    
Affiliation:
Department of Cell Biology, Center for Cardiovascular and Muscle Research, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
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MeSH Terms
Descriptor/Qualifier:
Angiotensin II / metabolism*
Angiotensinogen / genetics
Animals
Cardiomegaly / genetics,  metabolism*,  pathology
Extracellular Matrix / metabolism,  pathology
Fibroblasts / metabolism,  pathology
Fibrosis / metabolism,  pathology
Heterozygote
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myosin Heavy Chains / genetics
STAT3 Transcription Factor / metabolism
Signal Transduction / physiology
Smad3 Protein / metabolism
Transcription Factors / genetics*,  metabolism*
Transcription, Genetic / physiology
Transforming Growth Factor beta1 / metabolism*
Ventricular Remodeling / genetics*
Grant Support
ID/Acronym/Agency:
HL073399/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Hexim1 protein, mouse; 0/Myosin Heavy Chains; 0/STAT3 Transcription Factor; 0/Smad3 Protein; 0/Smad3 protein, mouse; 0/Stat3 protein, mouse; 0/Transcription Factors; 0/Transforming Growth Factor beta1; 11002-13-4/Angiotensinogen; 11128-99-7/Angiotensin II
Comments/Corrections

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