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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Serum response factor neutralizes Pur- and Purβ-mediated repression of the fetal vascular smooth muscle -actin gene in stressed adult cardiomyocytes

Aiwen Zhang,¹ Jason J. David,¹ Sukanya V. Subramanian,¹ Xiaoying Liu,¹ Matthew D. Fuerst,¹ Xue Zhao,⁴ Carl V. Leier,² Charles G. Orosz,^3, Robert J. Kelm, Jr.,⁵ and Arthur R. Strauch¹

Departments of ¹Physiology and Cell Biology, ²Internal Medicine, and ³Surgery, the Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, Ohio; ⁴Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai, China; and ⁵Department of Medicine, College of Medicine, University of Vermont, Colchester, Vermont

Submitted 25 April 2007 ; accepted in final form 8 January 2008

Mouse hearts subjected to repeated transplant surgery and ischemia-reperfusion injury develop substantial interstitial and perivascular fibrosis that was spatially associated with dysfunctional activation of fetal smooth muscle -actin (SMA) gene expression in graft ventricular cardiomyocytes. Compared with cardiac fibroblasts in which nuclear levels of the Sp1 and Smad 2/3 transcriptional-activating proteins increased markedly after transplant injury, the most abundant SMA gene-activating protein in cardiomyocyte nuclei was serum response factor (SRF). Additionally, cardiac intercalated discs in heart grafts contained substantial deposits of Pur, an mRNA-binding protein and known negative modulator of SRF-activated SMA gene transcription. Activation of fetal SMA gene expression in perfusion-isolated adult cardiomyocytes was linked to elevated binding of a novel protein complex consisting of SRF and Pur to a purine-rich DNA element in the SMA promoter called SPUR, previously shown to be required for induction of SMA gene transcription in injury-activated myofibroblasts. Increased SRF binding to SPUR DNA plus one of two nearby CArG box consensus elements was observed in SMA-positive cardiomyocytes in parallel with enhanced Pur:SPUR protein:protein interaction. The data suggest that de novo activation of the normally silent SMA gene in reprogrammed adult cardiomyocytes is linked to elevated interaction of SRF with fetal-specific CArG and injury-activated SPUR elements in the SMA promoter as well as the appearance of novel Pur protein complexes in both the nuclear and cytosolic compartments of these cells.

smooth muscle actin; cardiac fibrosis; cardiac transplant; gene transcription