Myocardial fibrosis in transforming growth factor‐β1 (TGF‐β1) transgenic mice is associated with inhibition of interstitial collagenase

摘要: BACKGROUND TGF-beta(1) mediates effects on fibroblast proliferation and collagen synthesis in the myocardium. The extracellular matrix remodeling depends fibrillar degrading metalloproteinases (MMPs) their inhibitors (TIMPs). vivo of MMP/TIMP system overexpressing transgenic mice were studied. METHODS Male Alb/TGF-beta(1)(cys(223,225)ser) (TG) nontransgenic controls (C; 8 weeks) examined. Protein expression type I, -III, interstitial collagenase (Int Coll), MMP-2, -9, TIMP-1, -2, -4 as well enzyme activity (MMP-2, -9) measured (Western blots, zymographic assays). mRNA MMP-9 was studied with Light-Cycler based real-time PCR. RESULTS Overexpression resulted a 10-fold increase plasma seven-fold myocardial concentrations. Relative heart weights increased (mg g(-1): 7.8 +/- 0.4 vs. 4.8 0.6, n = 6; P < 0.01) TG compared to C. Collagen I III (1.9-fold 1.7-fold) controls. Interstitial protein (- 91%) (-75%) reduced (P 0.05-P 0.001). Gelatinase MMP-9) not significantly alterated. MMP-inhibitors 2.5-fold (TIMP-1, -4) 6-fold (TIMP-2) TG. CONCLUSIONS produces fibrosis vivo. This effect is only produced by stimulation formation: complex regulation MMP TIMP interaction, namely decrease an enhanced inhibition levels TIMPs, are involved. These mechanisms optional targets for therapeutic interventions diseases.