Abstract
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.
Highlights
CLP-1 heterozygous mice exhibit enhanced susceptibility to cardiac stress
This report provides evidence that CLP-1 plays a significant role in modulation of the disease processes in left ventricular remodeling and fibrosis during cardiac hypertrophy due to its regulatory effects on pTEFb activity controlling transcription elongation, considered to be the primary site for eukaryotic gene control
Because CLP-1-mediated control of pTEFb is universal, targeting genes associated with left ventricular hypertrophy (LVH) and fibrogenic responses perhaps arise from the interplay among TGF-/Smad3/Jak2 signaling for the context-specific control of pTEFb activity
Summary
CLP-1 heterozygous mice exhibit enhanced susceptibility to cardiac stress. Results: Angiotensin-II-induced left ventricular hypertrophy and fibrosis were enhanced, and the Smad and Stat signaling was stimulated in CLP-1ϩ/Ϫ mice. Increased in various deleterious conditions to the heart, such as pressure and volume overload [6, 7] and heart failure [8], is known to block TGF--induced nuclear localization of the causes of Smads and the inhibition of TGF--induced ECM proteins [9] It appears that Smad signaling plays a prominent role in AngII-moderated hypertrophic response. It was reported that the serine kinase activity of Cdk targets RNA polymerase II and the conserved serine residues of the polylinker region in Smad3 [18], leading to speculation that CLP-1-mediated changes in pTEFb activity may trigger Cdk9dependent Smad signaling that can modulate collagen expression and fibrosis. Our findings underscore the critical role of CLP-1 in remodeling of the genetic response during hypertrophy and fibrosis
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