Inhibition of farnesyl pyrophosphate synthase improves pressure overload induced chronic cardiac remodeling.

Chen-Ze Zhao,Jie Ding,Bin Chen,Dong-Pu Dai,Jian Yang,Xu-Ming Zhao,Shen-Jiang Hu,Yun Mou,Huan-Dong Wu

doi:10.1038/srep39186

Abstract

Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. In our previous studies, we find that inhibition of FPPS attenuates angiotensin II-induced cardiac hypertrophy and fibrosis by suppressing RhoA while FPPS and Ras are up-regulated in pressure overload rats. In this study, we evaluate the effects and mechanisms of FPPS inhibition in pressure overload mice. Male FPPS-small interfering RNA (SiRNA) transgenic (Tg) mice and non-transgenic littermate control (NLC) were randomly divided into suprarenal abdominal aortic constriction (AAC) group and sham operation group. 12 weeks following AAC, mice were sacrificed by cervical dislocation. Histological and echocardiographic assessments showed that inhibition of FPPS improved chronic cardiac remodeling which was induced by AAC. The reductions of Ras farnesylation and GTP-Ras, as well as their downstream extracellular signal-related kinases 1/2 (ERK1/2) expression were observed in the heart of Tg-AAC mice compared with NLC-AAC mice, along with the reduction of fetal gene expression. We provide here important experimental evidence that inhibition of FPPS improves AAC induced chronic cardiac remodeling and fibrosis by the reduction of farnesylated Ras and the downregulation of Ras-ERK1/2 pathway.

Highlights

IntroductionWe find that inhibition of Farnesyl pyrophosphate synthase (FPPS) attenuates angiotensin II-induced cardiac hypertrophy and fibrosis by suppressing RhoA while FPPS and Ras are up-regulated in pressure overload rats
Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway
The expression of heart failure markers, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) were all increased as accessed by qPCR (Fig. 2A–C)

Summary

Introduction

We find that inhibition of FPPS attenuates angiotensin II-induced cardiac hypertrophy and fibrosis by suppressing RhoA while FPPS and Ras are up-regulated in pressure overload rats. We evaluate the effects and mechanisms of FPPS inhibition in pressure overload mice. Histological and echocardiographic assessments showed that inhibition of FPPS improved chronic cardiac remodeling which was induced by AAC. We provide here important experimental evidence that inhibition of FPPS improves AAC induced chronic cardiac remodeling and fibrosis by the reduction of farnesylated Ras and the downregulation of RasERK1/2 pathway. Interfering RNA transgenic mice[14] and their non-transgenic littermate control which subjected to abdominal aortic constriction or sham operation were used to further investigate the effect of FPPS in pressure overload

Methods

Results

Conclusion