P21waf1/cip1/sdi1 as a central regulator of inducible smooth muscle actin expression and differentiation of cardiac fibroblasts to myofibroblasts.
The phenotypic switch of cardiac fibroblasts (CFs) to myofibroblasts is essential for normal and pathological wound healing. Relative hyperoxic challenge during reoxygenation causes myocardial remodeling. Here, we sought to characterize the novel O(2)-sensitive molecular mechanisms responsible for triggering the differentiation of CFs to myofibroblasts. Exposure of CFs to hyperoxic challenge-induced transcription of smooth muscle actin (SMA) and enhanced the stability of both Acta2 transcript as well as of SMA protein. Both p21 deficiency as well as knockdown blunted hyperoxia-induced Acta2 and SMA response. Strikingly, overexpression of p21 alone markedly induced differentiation of CFs under normoxia. Overexpression of p21 alone induced SMA transcription by down-regulating YB1 and independent of TGFbeta1. In vivo, hyperoxic challenge induced p21-dependent differentiation of CFs to myofibroblasts in the infarct boundary region of ischemia-reperfused heart. Tissue elements were laser-captured from infarct boundary and from a noninfarct region 0.5 mm away. Reperfusion caused marked p21 induction in the infarct region. Acta2 as well as SMA expression were markedly up-regulated in CF-rich infarct boundary region. Of note, ischemia-reperfusion-induced up-regulation of Acta2 in the infarct region was completely abrogated in p21-deficient mice. This observation establishes p21 as a central regulator of reperfusion-induced phenotypic switch of CFs to myofibroblasts.
Roy
Sashwati
S
Laboratory of Molecular Medicine, Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, OH 43210, USA.
Khanna
Savita
S
Rink
Trenton
T
Radtke
Jared
J
Williams
W Taylor
WT
Biswas
Sabyasachi
S
Schnitt
Rebecca
R
Strauch
Arthur R
AR
Sen
Chandan K
CK
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005347:Fibroblasts; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics
D000199:Actins; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D010100:Oxygen