RGD Reference Report - Mechanism of the inhibitory effect of atorvastatin on endoglin expression induced by transforming growth factor-beta1 in cultured cardiac fibroblasts.

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Mechanism of the inhibitory effect of atorvastatin on endoglin expression induced by transforming growth factor-beta1 in cultured cardiac fibroblasts.
Authors:	Shyu, KG Wang, BW Chen, WJ Kuan, P Hung, CR
Citation:	Shyu KG, etal., Eur J Heart Fail. 2010 Mar;12(3):219-26. doi: 10.1093/eurjhf/hfq011.
RGD ID:	7257540
Pubmed:	PMID:20156938 (View Abstract at PubMed)
DOI:	DOI:10.1093/eurjhf/hfq011 (Journal Full-text)
AIMS: Transforming growth factor-beta1 (TGF-beta1) and endoglin play a causal role in promoting cardiac fibrosis. Atorvastatin has been shown to have an inhibitory effect on cardiac fibroblasts in vitro. However, the effects of statins on TGF-beta1 and endoglin are poorly understood. We therefore sought to investigate the molecular mechanisms of atorvastatin on endoglin expression after TGF-beta1 stimulation in cardiac fibroblasts. METHODS AND RESULTS: Cultured cardiac fibroblasts were obtained from adult male Sprague-Dawley rat hearts. TGF-beta1 stimulation increased endoglin and collagen I expression and atorvastatin inhibited the induction of endoglin and collagen I by TGF-beta1. Phosphatidylinositol-3 kinase (PI-3) and Akt inhibitors (wortmannin and Akt inhibitor X) completely attenuated the endoglin protein expression induced by TGF-beta1. TGF-beta1 induced phosphorylation of PI-3 kinase and Akt, while atorvastatin and wortmannin and Akt inhibitor X inhibited the phosphorylation of PI-3 kinase and Akt induced by TGF-beta1. The gel shift and promoter activity assay showed that TGF-beta1 increased Smad3/4-binding activity and endoglin promoter activity, while wortmannin and atorvastatin inhibited the Smad3/4-binding activity and endoglin promoter activity induced by TGF-beta1. TGF-beta1 increased collagen I protein expression, while endoglin siRNA attenuated collagen I protein expression induced by TGF-beta1. Atorvastatin decreased left ventricular TGF-beta1, endoglin, and collagen I protein expression and fibrotic area in a rat model of volume overload heart failure. CONCLUSION: Atorvastatin inhibits endoglin expression through the inhibition of PI-3 kinase, Akt, and Smad3 phosphorylation, and reduced Smad3/4 binding activity and endoglin promoter activity in cardiac fibroblasts.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
ENG	Human	congestive heart failure	treatment	ISO	Eng (Rattus norvegicus)		RGD
ENG	Human	congestive heart failure		ISO	Eng (Rattus norvegicus)	protein:increased expression:heart left ventricle (rat)	RGD
Eng	Rat	congestive heart failure	treatment	IDA			RGD
Eng	Rat	congestive heart failure		IEP		protein:increased expression:heart left ventricle (rat)	RGD
Eng	Mouse	congestive heart failure	treatment	ISO	Eng (Rattus norvegicus)		RGD
Eng	Mouse	congestive heart failure		ISO	Eng (Rattus norvegicus)	protein:increased expression:heart left ventricle (rat)	RGD

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Eng	Rat	positive regulation of collagen biosynthetic process		IMP			RGD
Eng	Rat	response to xenobiotic stimulus		IEP		atorvastatin	RGD

Objects Annotated

Genes (Rattus norvegicus)

Eng (endoglin)

Genes (Mus musculus)

Eng (endoglin)

Genes (Homo sapiens)

ENG (endoglin)

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Mechanism of the inhibitory effect of atorvastatin on endoglin expression induced by transforming growth factor-beta1 in cultured cardiac fibroblasts.