期刊
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
卷 39, 期 10, 页码 851-859出版社
WILEY
DOI: 10.1111/j.1365-2362.2009.02183.x
关键词
Cardiac remodelling; hypertrophy; interstitial remodelling; transforming growth factor beta-1; transgenic mouse model
资金
- Bundesministerium fur Bildung und Forschung
- Boehringer-Ingelheim GmbH
- Deutsche Forschungsgemeinschaft
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据