Abstract

BACKGROUND
Experimental cell therapy attenuates maladaptive cardiac remodeling and improves heart function. Paracrine mechanisms have been proposed. The effect of cell therapy on post infarction cardiac fibroblast and extracellular matrix (ECM) regulation was examined.
METHODS AND RESULTS
Vascular smooth muscle cells (VSMC) were injected into the border zone of subacute infarcted syngeneic Fischer rat hearts and compared with medium-injected controls. Twelve weeks post injection, cell-treated hearts showed preserved ECM content and attenuated structural chamber remodeling. Myofibroblast activation (α-smooth muscle actin expression) was decreased significantly, while basic fibroblast growth factor (bFGF) expression, a known inhibitor of transforming growth factor β-1-induced fibroblast differentiation, was increased. Matrix metalloproteinase-2 expression and activation by gelatin zymography was unchanged between groups, while its endogenous inhibitor, tissue inhibitors of matrix metalloproteinase (TIMP)-2, showed both increased expression and enhanced inhibitory capacity in cell-treated hearts. To define paracrine mechanisms, in vitro effects of VSMC conditioned media on myofibroblast activation were assessed by 3-D collagen gel contraction assay. VSMC conditioned media significantly inhibited collagen contraction, while a specific bFGF inhibitor abolished this paracrine response. TIMP-2 induced collagen contraction, but the effect was suppressed in the presence of bFGF.
CONCLUSIONS
Extracellular matrix dysregulation post myocardial infarction is improved by cell therapy. These data suggest that cell transplantation attenuates myofibroblast activation and subsequent maladaptive structural chamber remodeling through paracrine mechanisms involving bFGF and TIMP-2.

Links

Publisher Full Text

Publisher Full Text

Authors

Fedak PW, Bai L, Turnbull J, Ngu J, Narine K, Duff HJ

Institution

Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Alberta, Canada. paul.fedak@gmail.com

Source

Circulation. Heart failure 5:3 2012 May 1 pg 349-56

MeSH

Actins
Animals
Cell Differentiation
Extracellular Matrix
Fibroblast Growth Factor 2
Male
Matrix Metalloproteinase 2
Models, Animal
Muscle, Smooth, Vascular
Myocardial Contraction
Myocardial Infarction
Myofibroblasts
Paracrine Communication
Rats
Rats, Inbred F344
Tissue Inhibitor of Metalloproteinase-2
Tissue Therapy
Ventricular Remodeling

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22508775