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Does neuroendocrine antagonism with telmisartan or metoprolol reduce hypertrophic and fibrotic phenotypes in TGF-beta1 transgenic mice?
Does neuroendocrine antagonism with telmisartan or metoprolol reduce hypertrophic and fibrotic phenotypes in TGF-beta1 transgenic mice?
In a transgenic mouse model of TGF-beta1 overexpression, AT1 antagonism with telmisartan reduced both hypertrophy and interstitial fibrosis, whereas beta1-blockade with metoprolol primarily reduced hypertrophy.
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Telmisartan may reduce interstitial fibrosis beyond hypertrophy in this TGF-β1 model; hypothesis-generating for AT1 blockade, pending clinical translation.
BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) is involved in interstitial remodelling promoting collagen synthesis and suppressing collagen degradation by inhibition of collagenases. TGF-beta1 mediates angiotensin II-dependent effects and modulates beta1-adrenergic signalling. To study the effect of neuroendocrine antagonism on TGF-beta-induced hypertrophic and fibrotic phenotype, we treated TGF-beta1 (Cys223,225Ser) transgenic mice (TGF-beta1-TG) with either the beta1-receptor blocker metoprolol (MET), the angiotensin II type I (AT1)-receptor antagonist telmisartan (TEL) or an antibody blocking TGF-beta1 signalling (TGFbeta1-sR-Ab). MATERIAL AND METHODS: Transforming growth factor-beta1-TG mice (8 weeks) overexpressing TGF-beta1 were treated with either TEL (10 mg kg(-1)), MET (350 mg kg(-1)) or a soluble TGF-beta1 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-beta1-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-beta1-TG but inhibited by TEL (TIMP-1 and TIMP-4) and MET (TIMP-1), while collagenase activity was decreased in TGF-beta1-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-beta1-TG mice by normalizing MMP/TIMP ratio. beta1-Adrenergic inhibition by MET as well as TGF-beta1 antagonism induced antihypertrophic rather than antifibrotic effects. Inhibition of both renin-angiotensin system and beta1-adrenergic system may exert different but synergistic effects to reduce myocardial remodelling.
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Seeland et al. (2009) studied this question.
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