Inhibition of farnesyl pyrophosphate synthase attenuates angiotensin II-induced cardiac hypertrophy and fibrosis in vivo.

Abstract

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.

• Authors: Jian Yang, Huan-Huan Zhu, Guo-Ping Chen, Yang Ye, Chen-Ze Zhao, Yun Mou, Shen-Jiang Hu
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 45 Issue 3 Pg. 657-66 (Mar 2013) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 23277274 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Terpenes
• Transforming Growth Factor beta1
• Angiotensin II
• Natriuretic Peptide, Brain
• Atrial Natriuretic Factor
• Geranyltranstransferase
• p38 Mitogen-Activated Protein Kinases
• RhoA protein, mouse
• rho GTP-Binding Proteins
• rhoA GTP-Binding Protein
• Alendronate

Topics

• Alendronate (pharmacology)
• Angiotensin II (administration & dosage, metabolism)
• Animals
• Atrial Natriuretic Factor (metabolism)
• Cardiomegaly (genetics, metabolism, nursing, pathology)
• Contraindications
• Fibrosis (genetics, metabolism, nursing, pathology)
• Gene Expression Regulation
• Geranyltranstransferase (antagonists & inhibitors, genetics, metabolism, supply & distribution)
• Humans
• Male
• Mice
• Myocytes, Cardiac (metabolism, pathology)
• Natriuretic Peptide, Brain (metabolism)
• Signal Transduction
• Terpenes (metabolism)
• Transforming Growth Factor beta1 (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)
• rho GTP-Binding Proteins (metabolism)
• rhoA GTP-Binding Protein