Cardiac-specific overexpression of farnesyl pyrophosphate synthase induces cardiac hypertrophy and dysfunction in mice.

Jian Yang, Yun Mou, Tao Wu, Yang Ye, Jun-Chang Jiang, Chen-Ze Zhao, Huan-Huan Zhu, Chang-Qing Du, Liang Zhou, Shen-Jiang Hu

Institute of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79, Qing-Chun Road, Hangzhou 310003, China.

Cardiovascular research 2013 Mar 1

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Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. In our previous study, we found that inhibition of FPPS attenuates cardiac hypertrophy in spontaneously hypertensive rats (SHRs) and prevents angiotensin (Ang) II-induced hypertrophy in cardiomyocytes. Here, we further investigate the role of FPPS in cardiac hypertrophy and heart failure (HF) using a transgenic (Tg) model, and its mechanisms. Tg mice with cardiac-specific expression of FPPS were studied as an experimental model. The results showed that Tg mice with overexpression of FPPS exhibited cardiac hypertrophy, fibrosis, and HF, as well as increased synthesis of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate in heart tissue. These pathological changes were associated with the activation of RhoA and other known kinases in the hypertrophic signalling pathway, such as extracellular signal-related kinases 1/2 and p38. Adenoviral infection of FPPS in cultured neonatal cardiomyocytes induced a hypertrophic response characterized by an increased cell size and an increased extent of sarcomeric organization, as well as an increased activation profile of small GTPases and downstream protein kinases concordant with those seen in vivo. Further investigation showed a marked increase of FPPS protein levels in hypertrophic ventricles of patients with valvular heart disease. Taken together, these results suggest that FPPS may function as a potent regulator in myocardial remodelling. The FPPS-regulated signalling pathway is relevant to the pathological changes in cardiac hypertrophy and HF.

Citation

Jian Yang, Yun Mou, Tao Wu, Yang Ye, Jun-Chang Jiang, Chen-Ze Zhao, Huan-Huan Zhu, Chang-Qing Du, Liang Zhou, Shen-Jiang Hu. Cardiac-specific overexpression of farnesyl pyrophosphate synthase induces cardiac hypertrophy and dysfunction in mice. Cardiovascular research. 2013 Mar 1;97(3):490-9