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.
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.
Department of Cell Biology, Center for Cardiovascular and Muscle Research, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
Eduardo
E
Mascareno
Josephine
J
Galatioto
Inna
I
Rozenberg
Louis
L
Salciccioli
Haroon
H
Kamran
Jason M
JM
Lazar
Fang
F
Liu
Thierry
T
Pedrazzini
M A Q
MA
Siddiqui
D000804:Angiotensin II / Q000378:metabolism*; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018995:Myosin Heavy Chains / Q000235:genetics; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000235:genetics*
C118642:Hexim1 protein, mouse; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C494087:Stat3 protein, mouse; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000808:Angiotensinogen; D000804:Angiotensin II; D018995:Myosin Heavy Chains