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

被引：27

作者：

Seeland, U. ^{[1
]}

Schaeffer, A. ^{[1
]}

Selejan, S. ^{[1
]}

Hohl, M. ^{[1
]}

Reil, J. -C. ^{[1
]}

Mueller, P. ^{[1
]}

Rosenkranz, S. ^{[2
]}

Boehm, M. ^{[1
]}

机构：

[1] Univ Klinikum Saarlandes, Innere Med Klin 3, D-66421 Homburg, Germany

[2] Univ Cologne, Innere Med Klin 3, D-50924 Cologne, Germany

来源：

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION | 2009年 / 39卷 / 10期

关键词：

Cardiac remodelling; hypertrophy; interstitial remodelling; transforming growth factor beta-1; transgenic mouse model; TRANSFORMING GROWTH FACTOR-BETA(1); RAT CARDIAC FIBROBLASTS; ANGIOTENSIN-II; TGF-BETA; MYOCARDIAL FIBROSIS; INDUCED HYPERTROPHY; GROWTH-FACTOR-BETA-1; EXPRESSION; INHIBITOR; MYOCYTES;

D O I：

10.1111/j.1365-2362.2009.02183.x

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

P>Background Transforming growth factor-beta 1 (TGF-beta 1) is involved in interstitial remodelling promoting collagen synthesis and suppressing collagen degradation by inhibition of collagenases. TGF-beta 1 mediates angiotensin II-dependent effects and modulates beta 1-adrenergic signalling. To study the effect of neuroendocrine antagonism on TGF-beta-induced hypertrophic and fibrotic phenotype, we treated TGF-beta 1 (Cys223,225Ser) transgenic mice (TGF-beta 1-TG) with either the beta 1-receptor blocker metoprolol (MET), the angiotensin II type I (AT1)-receptor antagonist telmisartan (TEL) or an antibody blocking TGF-beta 1 signalling (TGF beta 1-sR-Ab). Material and Methods Transforming growth factor-beta 1-TG mice (8 weeks) overexpressing TGF-beta 1 were treated with either TEL (10 mg kg-1), MET (350 mg kg-1) or a soluble TGF-beta 1 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-beta 1-TG mice, myocardial interstitial total collagen content was fourfold elevated compared to that of controls (P < 0 center dot 05) and was lowered under the treatment with TEL (P < 0 center dot 05). Protein expression of TIMP-1 and -4 was increased in TGF-beta 1-TG but inhibited by TEL (TIMP-1 and TIMP-4) and MET (TIMP-1), while collagenase activity was decreased in TGF-beta 1-TG and normalized by treatment with TEL (MMP-1 and MMP-13) and MET (MMP-1) (P < 0 center dot 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-beta 1-TG mice by normalizing MMP/TIMP ratio. beta 1-Adrenergic inhibition by MET as well as TGF-beta 1 antagonism induced antihypertrophic rather than antifibrotic effects. Inhibition of both renin-angiotensin system and beta 1-adrenergic system may exert different but synergistic effects to reduce myocardial remodelling.

引用

页码：851 / 859

页数：9

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