Collagen accumulation after myocardial infarction: effects of ETA receptor blockade and implications for early remodeling.
OBJECTIVE
Endothelin A (ETA) receptor blockade started early after myocardial infarction (MI) promotes adverse left ventricular (LV) dilatation. We tested the hypothesis that inhibition of ETA receptors during the early phase of healing affects collagen synthesis and accumulation, and induces expansion of infarcted myocardium.


METHODS
Starting 3 h after coronary ligation, female Wistar rats were treated with the selective ETA receptor antagonist LU 135252 (30 mg/kg body wt/day) or placebo. A period of 7 days after MI, hemodynamic, morphometric and biochemical studies were performed.


RESULTS
ET(A) receptor blockade enhanced infarct expansion index and decreased LV systolic function. Infarct scar of LU 135252-treated rats displayed decreased gene expression of fibrillar type I/III collagens and of transforming growth factor-beta(1) (TGF-beta(1)). Collagen content in the infarct scar and border regions was lower after ETA inhibition. In addition, Western blot analysis revealed, after ETA receptor blockade, enhanced matrix metalloproteinases MMP-13, and MMP-2 expression in the infarcted LV myocardium.


CONCLUSIONS
These data demonstrate that endothelin stimulates collagen accumulation at the site of infarction. Decreased collagen and TGF-beta(1) gene expression, associated with enhanced infarct expansion and MMP up-regulation likely contributes to ETA receptor blockade-mediated deleterious effects on ventricular remodeling after infarction.
Fraccarollo
Daniela
D
Medizinische Klinik, Julius-Maximilians-Universität Würzburg, Würzburg, Germany. d.fraccarollo@medizin.uni-wuerzburg.de
Galuppo
Paolo
P
Bauersachs
Johann
J
Ertl
Georg
G
D000818:Animals; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D005260:Female; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D023421:Models, Animal; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010666:Phenylpropionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D020257:Ventricular Remodeling
D024042:Collagen Type I; D024061:Collagen Type III; D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; C508962:Tgfb1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019716:Tissue Inhibitor of Metalloproteinase-2; C107831:darusentan; D003094:Collagen; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat; D020778:Matrix Metalloproteinase 2