Effects of AT1- and β-adrenergic receptor antagonists on TGF-β1-induced fibrosis in transgenic mice

• Published in: European journal of clinical investigation Vol. 39; no. 10; pp. 851 - 859
• Main Authors: Seeland, U., Schäffer, A., Selejan, S., Hohl, M., Reil, J.-C., Müller, P., Rosenkranz, S., Böhm, M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2009; Wiley-Blackwell
• Subjects: Biological and medical sciences; Cardiac remodelling; General aspects; hypertrophy; interstitial remodelling; Medical sciences; transforming growth factor β-1; transgenic mouse model; Heart; Animal model; Transforming growth factor β; transgenic mouse model; Rodentia; Transgenic animal; Remodeling; Cardiac remodelling; β-Adrenergic receptor; Medicine; Vertebrata; Mammalia; Mouse; Fibrosis; transforming growth factor β-1; Interstitial; Circulatory system; Transforming growth factor β1; interstitial remodelling; Beta blocking agent; Hypertrophy
• ISSN: 0014-2972; 1365-2362
• DOI: 10.1111/j.1365-2362.2009.02183.x

Background  Transforming growth factor‐β1 (TGF‐β1) is involved in interstitial remodelling promoting collagen synthesis and suppressing collagen degradation by inhibition of collagenases. TGF‐β1 mediates angiotensin II‐dependent effects and modulates β1‐adrenergic signalling. To study the effect of neuroendocrine antagonism on TGF‐β‐induced hypertrophic and fibrotic phenotype, we treated TGF‐β1 (Cys223,225Ser) transgenic mice (TGF‐β1‐TG) with either the β1‐receptor blocker metoprolol (MET), the angiotensin II type I (AT1)‐receptor antagonist telmisartan (TEL) or an antibody blocking TGF‐β1 signalling (TGFβ1‐sR‐Ab). Material and Methods  Transforming growth factor‐β1‐TG mice (8 weeks) overexpressing TGF‐β1 were treated with either TEL (10 mg kg−1), MET (350 mg kg−1) or a soluble TGF‐β1 receptor antibody (1 mg kg−1) for 6 weeks. Morphological analyses of interstitium and cardiomyocytes were related to expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) by immunoblotting and zymography. Results  In TGF‐β1‐TG mice, myocardial interstitial total collagen content was fourfold elevated compared to that of controls (P < 0·05) and was lowered under the treatment with TEL (P < 0·05). Protein expression of TIMP‐1 and ‐4 was increased in TGF‐β1‐TG but inhibited by TEL (TIMP‐1 and TIMP‐4) and MET (TIMP‐1), while collagenase activity was decreased in TGF‐β1‐TG and normalized by treatment with TEL (MMP‐1 and MMP‐13) and MET (MMP‐1) (P < 0·05). Morphometric measurements of cardiomyocyte diameter and area demonstrated similar antihypertrophic effects for all treatment groups. Conclusion  The AT1‐antagonist TEL reduced myocardial hypertrophy and interstitial fibrosis in TGF‐β1‐TG mice by normalizing MMP/TIMP ratio. β1‐Adrenergic inhibition by MET as well as TGF‐β1 antagonism induced antihypertrophic rather than antifibrotic effects. Inhibition of both renin‐angiotensin system and β1‐adrenergic system may exert different but synergistic effects to reduce myocardial remodelling.