Inhibition of farnesyl pyrophosphate synthase attenuates high glucose‑induced vascular smooth muscle cells proliferation.
The proliferation of vascular smooth muscle cells (VSMCs) is one of the main features of atherosclerosis accelerated by hyperglycemia. Our previous studies found that farnesyl pyrophosphate synthase (FPPS, EC 2.5.1.10), an essential enzyme in the mevalonate pathway, was upregulated in aorta media from diabetic mice along with the process of atherosclerosis. However, the exact role of FPPS in high glucose‑induced proliferation of VSMCs is largely unclear. In our study, we found that alendronate (an FPPS inhibitor) attenuated diabetic accelerated atherosclerosis in vivo and suppressed high glucose‑induced VSMCs proliferation in vitro. Moreover, in aorta from streptozotocin (STZ)‑induced diabetic mice, 16‑week treatment of alendronate decreased the activation of small GTPase (Ras, RhoA, and Rac1), but had no effect on the expression of cystathionine γ‑lyase (CSE), the pivotal H2S‑producing enzyme. Meanwhile, in VSMCs cultured in high glucose‑containing media, alendronate remarkably decreased total CoQ content, increased the H2S level, depressed small GTPases (Ras, RhoA, and Rac1) activation, but yet had no effect on expression of CSE. In conclusion, FPPS inhibition by alendronate attenuated the high glucose‑induced proliferation of VSMCs both in vivo and in vitro, probably though depressing H2S metabolism and suppressing small GTPases (Ras, RhoA, and Rac1) activation.
Department of Endocrinology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
Guo-Ping
GP
Chen
Department of Respirology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China.
Xiao-Qin
XQ
Zhang
Institute of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
Tao
T
Wu
Institute of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
Jie
J
Han
Department of Endocrinology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
Dan
D
Ye
D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001786:Blood Glucose / Q000032:analysis; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000473:pathology; D005260:Female; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005947:Glucose / Q000633:toxicity*; D006862:Hydrogen Sulfide / Q000032:analysis / Q000378:metabolism; D008055:Lipids / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013053:Spectrophotometry; D013311:Streptozocin / Q000633:toxicity; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism
D001786:Blood Glucose; D008055:Lipids; D014451:Ubiquinone; D013311:Streptozocin; D051228:Geranyltranstransferase; D020559:Monomeric GTP-Binding Proteins; D003542:Cystathionine gamma-Lyase; D005947:Glucose; D019386:Alendronate; D006862:Hydrogen Sulfide