Inhibition of farnesyl pyrophosphate synthase attenuates angiotensin II-induced cardiac hypertrophy and fibrosis in vivo
| Autor: | Jian Yang, Yun Mou, Huan-Huan Zhu, Guo-Ping Chen, Shen-Jiang Hu, Chen-Ze Zhao, Yang Ye |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
rho GTP-Binding Proteins MAPK/ERK pathway medicine.medical_specialty RHOA Farnesyl pyrophosphate Cardiomegaly p38 Mitogen-Activated Protein Kinases Biochemistry Muscle hypertrophy Transforming Growth Factor beta1 Mice chemistry.chemical_compound In vivo Fibrosis Internal medicine Natriuretic Peptide Brain medicine Animals Humans Myocytes Cardiac Alendronate biology Terpenes Angiotensin II Contraindications Geranyltranstransferase Cell Biology medicine.disease Endocrinology Gene Expression Regulation chemistry cardiovascular system biology.protein Mevalonate pathway rhoA GTP-Binding Protein Atrial Natriuretic Factor hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | The International Journal of Biochemistry & Cell Biology. 45:657-666 |
| ISSN: | 1357-2725 |
| DOI: | 10.1016/j.biocel.2012.12.016 |
| Popis: | Farnesyl pyrophosphate synthase (FPPS), as a key branchpoint of the mevalonate pathway, catalyzes the synthesis of isoprenoid intermediates. The isoprenoid intermediates are needed for protein isoprenylation to participate in cardiac remodeling. We have previously demonstrated that both knockdown of FPPS with small interfering RNA and inhibition of FPPS by alendronate could prevent Ang II-induced hypertrophy in cultured cardiomyocytes. In this study, we evaluated the effects of FPPS inhibition in Ang II-mediated cardiac hypertrophy and fibrosis in vivo. Wild type mice were separately treated with saline, Ang II (2.88 mg/kg per day), FPPS inhibitor alendronate (0.1 mg/kg per day), or the combination of Ang II (2.88 mg/kg per day) and alendronate (0.1 mg/kg per day) for 4 weeks. The results showed that Ang II increased FPPS expression, and the increases of Ang II-induced synthesis of the isoprenoid intermediates, FPP and GGPP, were significantly inhibited by FPPS inhibitor. In the meantime, FPPS inhibition attenuated Ang II-mediated cardiac hypertrophy and fibrosis as indexed by the heart weight to body weight ratio, echocardiographic parameters, histological examinations and expression of ANP and BNP mRNA. Furthermore, it was also found that FPPS inhibitor attenuated Ang II-induced increases of RhoA activity and p-38 MAPK phosphorylation and TGF-β1 mRNA expression. In conclusion, FPPS might play an important role in Ang II-induced cardiac hypertrophy and fibrosis in vivo, at least in part through RhoA, p-38 MAPK and TGF-β1. |
| Databáze: | OpenAIRE |
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