© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Reprogramming of vascular smooth muscle 
-actin gene expression as an early indicator of dysfunctional remodeling following heart transplant
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) 
-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 and Purβ VSM -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 -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 -actin. Cardiomyocytes isolated from adult, non-transplanted mouse hearts not only exhibited less VSM -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 -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
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  X. Liu, R. J. Kelm Jr., and A. R. Strauch Transforming Growth Factor {beta}1-mediated Activation of the Smooth Muscle {alpha}-Actin Gene in Human Pulmonary Myofibroblasts Is Inhibited by Tumor Necrosis Factor-{alpha} via Mitogen-activated Protein Kinase Kinase 1-dependent Induction of the Egr-1 Transcriptional Repressor Mol. Biol. Cell, April 15, 2009; 20(8): 2174 - 2185. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Zhang, J. J. David, S. V. Subramanian, X. Liu, M. D. Fuerst, X. Zhao, C. V. Leier, C. G. Orosz, R. J. Kelm Jr., and A. R. Strauch Serum response factor neutralizes Pur{alpha}- and Pur{beta}-mediated repression of the fetal vascular smooth muscle {alpha}-actin gene in stressed adult cardiomyocytes Am J Physiol Cell Physiol, March 1, 2008; 294(3): C702 - C714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Knapp, J. E. Ramsey, S.-X. Wang, A. R. Strauch, and R. J. Kelm Jr. Structure-Function Analysis of Mouse Pur II: CONFORMATION ALTERING MUTATIONS DISRUPT SINGLE-STRANDED DNA AND PROTEIN INTERACTIONS CRUCIAL TO SMOOTH MUSCLE {alpha}-ACTIN GENE REPRESSION J. Biol. Chem., December 7, 2007; 282(49): 35899 - 35909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Ramsey, M. A. Daugherty, and R. J. Kelm Jr. Hydrodynamic Studies on the Quaternary Structure of Recombinant Mouse Purbeta J. Biol. Chem., January 19, 2007; 282(3): 1552 - 1560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Knapp, J. E. Ramsey, S.-X. Wang, K. E. Godburn, A. R. Strauch, and R. J. Kelm Jr. Nucleoprotein Interactions Governing Cell Type-dependent Repression of the Mouse Smooth Muscle {alpha}-Actin Promoter by Single-stranded DNA-binding Proteins Pur{alpha} and Purbeta J. Biol. Chem., March 24, 2006; 281(12): 7907 - 7918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Zhang, X. Liu, J. G. Cogan, M. D. Fuerst, J. A. Polikandriotis, R. J. Kelm Jr., and A. R. Strauch YB-1 Coordinates Vascular Smooth Muscle {alpha}-Actin Gene Activation by Transforming Growth Factor {beta}1 and Thrombin during Differentiation of Human Pulmonary Myofibroblasts Mol. Biol. Cell, October 1, 2005; 16(10): 4931 - 4940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-X. Wang, P. K. Elder, Y. Zheng, A. R. Strauch, and R. J. Kelm Jr. Cell Cycle-mediated Regulation of Smooth Muscle {alpha}-Actin Gene Transcription in Fibroblasts and Vascular Smooth Muscle Cells Involves Multiple Adenovirus E1A-interacting Cofactors J. Biol. Chem., February 18, 2005; 280(7): 6204 - 6214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. V. Subramanian, J. A. Polikandriotis, R. J. Kelm Jr., J. J. David, C. G. Orosz, and A. R. Strauch Induction of Vascular Smooth Muscle {alpha}-Actin Gene Transcription in Transforming Growth Factor {beta}1-Activated Myofibroblasts Mediated by Dynamic Interplay between the Pur Repressor Proteins and Sp1/Smad Coactivators Mol. Biol. Cell, October 1, 2004; 15(10): 4532 - 4543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Andrassy, S. Kusaka, E. Jankowska-Gan, J. R. Torrealba, L. D. Haynes, B. R. Marthaler, R. C. Tam, B. M.-W. Illigens, N. Anosova, G. Benichou, et al. Tolerance to Noninherited Maternal MHC Antigens in Mice J. Immunol., November 15, 2003; 171(10): 5554 - 5561. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Kelm Jr., S.-X. Wang, J. A. Polikandriotis, and A. R. Strauch Structure/Function Analysis of Mouse Pur{beta}, a Single-stranded DNA-binding Repressor of Vascular Smooth Muscle {alpha}-Actin Gene Transcription J. Biol. Chem., October 3, 2003; 278(40): 38749 - 38757. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R Strauch Building better blood vessels: new insight on the molecular control of arteriogenesis Cardiovasc Res, September 1, 2003; 59(3): 532 - 533. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Roy, S. Khanna, A. A. Bickerstaff, S. V. Subramanian, M. Atalay, M. Bierl, S. Pendyala, D. Levy, N. Sharma, M. Venojarvi, et al. Oxygen Sensing by Primary Cardiac Fibroblasts: A Key Role of p21Waf1/Cip1/Sdi1 Circ. Res., February 21, 2003; 92(3): 264 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Briest Do we have a new early marker of chronic transplant dysfunction now? Cardiovasc Res, June 1, 2002; 54(3): 492 - 494. [Full Text] [PDF]
|
|