Study Of Mevalonate Pathway In The Heart Of Spontaneously Hypertensive Rats

Background:Farnesyl pyrophosphate synthase (FPPS), an essential enzyme in the mevalonate pathway, catalyzes the synthesis of isoprenoid intermediates. The latter is needed for isoprenylation of small GTPase. FPPS was reported to be upregulated in young spontaneously hypertensive rats (SHR) when compared with Wistar-Kyoto (WKY) rats, and this was accompanied by development of left ventricular hypertrophy. Alendronate is used in the osteoporosis and cancer metastasis, and is confirmed to exert its pharmacological function by inhibition of FPPS.Aim:To determined whether chronic inhibition of FPPS can improve the cardiac hypertrophy and fibrosis in SHRs and explore its underlying mechanism.Methods:Eighteen male SHRs were randomly divided into three groups consisting of the distilled water group (SHR-C), the low-dose (1 mg/kg/d) alendronate group (SLA), and the high-dose (10 mg/kg/d) alendronate group (SHA). Six male age- and weight- matched WKY rats were housed as controls (WKY-C). Blood pressures were monitored by the tail-cuff method every other week. Hemodynamic was tested by carotid artery catheteration. Whole heart weight and left heart weight were obtained and calculated for evaluation of cardiac hypertrophy. Collagen content and distribution were evaluated by hydroxyproline content and Masson's trichrome. Active RhoA was tested by the RhoA pull-down kit, and phosphorylated ERK1/2 was obtained by Western blot. The marks of pro-hypertrophy and pro-fibrosis were determined by real-time polymerase chain reaction.Results:Twelve-weeks of alendronate treatment attenuated the left ventricular weight to body weight ratio (LVW/BW), hydroxyproline content, collagen deposition in the interstitia, and gene expression of atrial natriuretic peptide, B-type natriuretic peptide, and procollagen type I/III in the SHR left ventricle, all of which were significantly higher in SHRs than in WKY rats. Furthermore, long-term treatment with an FPPS inhibitor significantly reduced RhoA activation, ERK phosphorylation, and TGF-β1 expression in the SHR left ventricle, all of which were upregulated more in SHRs than in WKY rats. In conclusion, chronic treatment with an FPPS inhibitor attenuates the development of cardiac hypertrophy and fibrosis, and the suppression of ERK1/2 phosphorylation and TGF-β1 expression with inhibition of RhoA activation may be an important mechanism.