Chronic inhibition of farnesyl pyrophosphate synthase attenuates cardiac hypertrophy and fibrosis in spontaneously hypertensive rats.
Farnesyl pyrophosphate synthase (FPPS), an essential enzyme in the mevalonate pathway, 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. Five-week-old rats were daily gavaged with vehicle or an FPPS inhibitor (alendronate, 1 or 10 mg/kg) and blood pressures was monitored by the tail-cuff method every other week. 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-beta1 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-beta1 expression with inhibition of RhoA activation may be an important mechanism.
Institute of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China.
Liang
L
Li
Guo-Ping
GP
Chen
Yin
Y
Yang
Yang
Y
Ye
Lei
L
Yao
Shen-Jiang
SJ
Hu
D019386:Alendronate / Q000008:administration & dosage; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology* / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005355:Fibrosis; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006973:Hypertension / Q000201:enzymology* / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D004791:Enzyme Inhibitors; D051228:Geranyltranstransferase; D019386:Alendronate