Effects of AT1- and beta-adrenergic receptor antagonists on TGF-beta1-induced fibrosis in transgenic mice.
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).


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.


CONCLUSIONS
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.
Seeland
U
U
Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany.
Schäffer
A
A
Selejan
S
S
Hohl
M
M
Reil
J-C
JC
Müller
P
P
Rosenkranz
S
S
Böhm
M
M
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D008790:Metoprolol / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010641:Phenotype; D012084:Renin-Angiotensin System / Q000187:drug effects; D000077333:Telmisartan; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
D001562:Benzimidazoles; D001565:Benzoates; D053773:Transforming Growth Factor beta1; D003094:Collagen; D008790:Metoprolol; D000077333:Telmisartan