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Cardiovascular Research 2002 54(3):539-548; doi:10.1016/S0008-6363(02)00270-5
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Reprogramming of vascular smooth muscle {alpha}-actin gene expression as an early indicator of dysfunctional remodeling following heart transplant

Sukanya V. Subramaniana, Robert J. Kelm, Jr.b, John A. Polikandriotisa, Charles G. Oroszc and Arthur R. Straucha,*

aDepartment of Physiology and Cell Biology and the Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA
bDepartment of Medicine, Colchester Research Facility, University of Vermont, Colchester, VT 05446, USA
cDepartment of Surgery and the Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA

* Corresponding author. Department of Physiology and Cell Biology, The Ohio State University, College of Medicine, 1645 Neil Avenue, Room 302, Columbus, OH 43210-1218, USA. Tel.: +1-614-292-3147; fax: +1-614-292-4888 strauch.1{at}osu.edu

Objective: Chronic rejection in cardiac allografts depletes vascular smooth muscle (VSM) {alpha}-actin from the coronary arterial smooth muscle bed while promoting its abnormal accumulation in cardiomyocytes and myofibroblasts. The objective was to determine if the newly discovered TEF1, MSY1, Pur{alpha} and Purβ VSM {alpha}-actin transcriptional reprogramming proteins (TRPs) were associated with development of chronic rejection histopathology in accepted murine cardiac allografts. Methods: A mouse heterotopic cardiac transplant model was employed using H2 locus-mismatched mouse strains (DBA/2 or FVB/N to C57BL/6). Recipients were immunosuppressed to promote long-term allograft acceptance and emergence of chronic rejection. Explanted grafts and isolated heart cells were evaluated for changes in the DNA-binding activity and subcellular distribution of VSM {alpha}-actin transcriptional regulatory proteins. Results: The DNA-binding activity of all four TRPs was high in the developing mouse ventricle, minimal in adult donor hearts and increased substantially within 30 days after transplantation. Immunohistologic analysis revealed nuclear localization of Purβ and MSY1 particularly in fibrotic areas of the allograft myocardium demonstrating extravascular accumulation of VSM {alpha}-actin. Cardiomyocytes isolated from adult, non-transplanted mouse hearts not only exhibited less VSM {alpha}-actin expression and lower levels of TRPs compared to isolated cardiac fibroblasts or neonatal cardiomyocytes, but also contained a novel size variant of the MSY1 protein. Conclusion: Accumulation of TRPs in cardiac allografts, particularly within the fibroblast-enriched myocardial interstitium, was consistent with their potential role in VSM {alpha}-actin gene reprogramming, fibrosis and dysfunctional remodeling following transplant. These nuclear protein markers could help stage peri-transplant cellular events that precede formation of graft-destructive fibrosis and coronary vasculopathy during chronic rejection.

KEYWORDS Transplantation; Gene expression; Myocytes; Remodeling; Fibrosis


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