Alteration of mevalonate pathway in proliferated vascular smooth muscle from diabetic mice: possible role in high-glucose-induced atherogenic process.
The proliferation of vascular smooth muscle cells (VSMCs) is one of the main features of atherosclerosis induced by high glucose. Mevalonate pathway is an important metabolic pathway that plays a key role in multiple cellular processes. The aim of this study was to define whether the enzyme expression in mevalonate pathway is changed in proliferated VSMCs during atherogenic process in diabetic mice. Diabetes was induced in BALB/c mice with streptozotocin (STZ, 50 mg/kg/day for 5 days). Induction of diabetes with STZ was associated with an increase of lesion area and media thickness after 8 and 16 weeks of diabetes. In aorta, there were overexpressions of some enzymes, including 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), farnesyl pyrophosphate synthase (FPPS), geranylgeranyl pyrophosphate synthase (GGPPS), farnesyltransferase (FNT), and geranylgeranyltransferase-1 (GGT-1), and unchanged expression of squalene synthase (SQS) and phosphor-3-hydroxy-3-methylglutaryl-coenzyme A reductase (P-HMGR) in 8 and 16 weeks of diabetes. In vitro, VSMCs were cultured and treated with different glucose concentrations for 48 h. High glucose (22.2 mM) induced VSMC proliferation and upregulation of HMGR, FPPS, GGPPS, FNT, and GGT-1 but did not change the expressions of SQS and P-HMGR. In conclusion, altered expression of several key enzymes in the mevalonate pathway may play a potential pathophysiological role in atherogenic process of diabetes macrovascular complication.
Department of Endocrinology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
Guo-Ping
0000-0003-3620-6724
GP
Chen
Department of Respirology, Zhejiang Provincial People's Hospital, Hangzhou 310014, China.
Xiao-Qin
XQ
Zhang
Institute of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
Tao
T
Wu
Institute of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
Liang
L
Li
Institute of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
Jie
J
Han
Department of Cardiology, Zhejiang Hospital, Hangzhou 310003, China.
Chang-Qing
CQ
Du
D000214:Acyl Coenzyme A / Q000378:metabolism; D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000628:therapy; D051231:Farnesyltranstransferase / Q000378:metabolism; D005260:Female; D051232:Geranylgeranyl-Diphosphate Geranylgeranyltransferase / Q000378:metabolism; D051228:Geranyltranstransferase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007249:Inflammation; D008055:Lipids / Q000737:chemistry; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*
D000214:Acyl Coenzyme A; D001786:Blood Glucose; D008055:Lipids; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D051228:Geranyltranstransferase; D051231:Farnesyltranstransferase; D051232:Geranylgeranyl-Diphosphate Geranylgeranyltransferase; D005947:Glucose; D008798:Mevalonic Acid