title: Platelet-derived growth factor blockade on cardiac remodeling following infarction.
abstract: Cardiac repair and remodeling occur following myocardial infarction (MI). Our previous study demonstrated that platelet-derived growth factor (PDGF)-A/-D and PDGF receptors (PDGFR) are increased in the infarcted heart, with cells expressing PDGFR primarily endothelial and fibroblast-like cells. In the present study, we tested the hypothesis that PDGF contributes to cardiac angiogenesis and fibrogenesis post-MI. Rats with experimental MI were treated with either a PDGFR antagonist (Imatinib, 40 mg/kg/day) or vehicle by gavage, and sham-operated rats served as the controls. Cardiac fibrogenesis, angiogenesis, and ventricular function were detected at weeks 1 and 4 post-MI. We found that (1) transforming growth factor (TGF)-β1, tissue inhibitors of metalloproteinases (TIMP)-1/-2, and type I collagen mRNA were all significantly increased in the infarcted heart at week 1 post-MI, while PDGFR blockade significantly reduced these fibrogenic mediators in the noninfarcted myocardium as compared to controls; (2) fibrosis developed in both the infarcted and noninfarcted myocardium at week 4 with PDGFR blockade significantly suppressing collagen volume in the noninfarcted myocardium; (3) angiogenesis was activated in the infarcted myocardium, particularly at week 1, and was not altered by treatment with imatinib; and (4) ventricular dysfunction was evident in MI rats at week 4, and mildly improved with imatinib treatment. These observations indicated that PDGF can contribute to the development of cardiac interstitial fibrosis in the noninfarcted myocardium, but does not alter scar formation in the infarcted myocardium. Further, this study suggests the potential therapeutic effects of PDGFR blockade on interstitial fibrosis of the infarcted heart.
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, The First Affiliate Hospital of Harbin Medical University, Harbin, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Zhao
authors.forename: Weixin
authors.initials: W
authors.lastname: Meng
authors.forename: Tieqiang
authors.initials: T
authors.lastname: Zhao
authors.forename: Yuanjian
authors.initials: Y
authors.lastname: Chen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ahokas
authors.forename: Hongyu
authors.initials: H
authors.lastname: Liu
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000068877:Imatinib Mesylate; D008222:Lymphokines / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D001549:Benzamides; D008222:Lymphokines; C498952:Pdgfd protein, rat; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C576839:TIMP1 protein, rat; C508962:Tgfb1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; C075278:platelet-derived growth factor A; D019716:Tissue Inhibitor of Metalloproteinase-2; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor