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Vol. 18, Issue 12, 4837-4846, December 2007

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p21^{waf1/cip1/sdi1} as a Central Regulator of Inducible Smooth Muscle Actin Expression and Differentiation of Cardiac Fibroblasts to Myofibroblasts

Sashwati Roy^*, Savita Khanna^*, Trenton Rink^*, Jared Radtke^*, W. Taylor Williams^*, Sabyasachi Biswas^*, Rebecca Schnitt^*, Arthur R. Strauch, and Chandan K. Sen^*

*Laboratory of Molecular Medicine, Department of Surgery, and Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, OH 43210

Submitted March 23, 2007; Revised August 1, 2007; Accepted September 11, 2007
Monitoring Editor: Carl-Henrik Heldin

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 O₂-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 TGFβ1. 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.

Address correspondence to: Chandan K. Sen (chandan.sen{at}osumc.edu).

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