Abstract
BackgroundVascular calcification is an independent risk factor for cardiovascular disease. Diabetes mellitus increases the incidence of vascular calcification; however, detailed molecular mechanisms of vascular calcification in diabetes mellitus remain unknown. We recently reported that bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) regulates osteoblast-like trans-differentiation of human coronary artery smooth muscle cells (HCASMCs).MethodsWe investigated the effect of a hydroxymethylglutaryl-coenzyme A reductase inhibitor (statin), commonly used in patients with atherosclerotic diseases and diabetes mellitus, on alkaline phosphatase (ALP) mRNA expression in aortas of streptozotocin-induced diabetic mice. We also investigated the effects of the statin, Rho-associated protein kinase (ROCK) inhibitors and BMPER knockdown on ALP mRNA expression and activity in HCASMCs cultured in high glucose-containing media.ResultsAlkaline phosphatase mRNA expression was increased in aortas of streptozotocin-induced diabetic mice, and the increase was inhibited by rosuvastatin. ALP mRNA expression and activity were increased in HCASMCs cultured in high glucose-containing media, and the increases were suppressed by rosuvastatin. This suppression was reversed by the addition of mevalonate or geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate. High glucose-increased ALP mRNA expression and activity were suppressed by ROCK inhibitors. Moreover, BMPER mRNA expression was increased in diabetic mouse aortas and in HCASMCs cultured in high glucose-containing media, but was not inhibited by rosuvastatin or ROCK inhibitors. Knockdown of BMPER suppressed high glucose-increased ALP activity, but not ROCK activity in HCASMCs.ConclusionsThere are at least two independent pathways in high glucose-induced ALP activation in HCASMCs: the Rho–ROCK signaling pathway and the BMPER-dependent pathway.
Highlights
Vascular calcification is an independent risk factor for cardiovascular disease
Rosuvastatin decreased alkaline phosphatase (ALP) mRNA expression in aortas of STZ‐induced type I diabetic mice We investigated the effect of rosuvastatin on ALP expression in aortas of STZ-induced type I diabetic mice
Administration of rosuvastatin significantly inhibited the increase in ALP mRNA expression (P < 0.05) (Fig. 1a)
Summary
Vascular calcification is an independent risk factor for cardiovascular disease. Vascular calcification is one of the common pathological changes of atherosclerosis and is an independent risk factor for cardiovascular disease. The incidence of vascular calcification increases with aging, smoking, hemodialysis, and diabetes mellitus. Detailed molecular mechanisms of vascular calcification in diabetes mellitus remain poorly understood. High glucose promotes trans-differentiation of vascular smooth muscle cells, which is thought to cause vascular calcification, and hyperinsulinemia and elevated advanced glycosylation end products may play a role in vascular calcification [1]. In addition to inhibiting cholesterol synthesis, statins block the synthesis of isoprenoid intermediates such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) [3]. FPP and GGPP serve as important lipid attachments for the posttranslational modification of a variety of proteins, including small GTPases [4]. In vitro studies have demonstrated that statins inhibit Rho by inhibiting GGPP, and thereby suppress its effector Rho-associated protein kinase (ROCK) [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
