MicroRNA-99a inhibits insulin-induced proliferation, migration, dedifferentiation, and rapamycin resistance of vascular smooth muscle cells by inhibiting insulin-like growth factor-1 receptor and mammalian target of rapamycin.
Patients with type 2 diabetes mellitus (T2DM) are characterized by insulin resistance and are subsequently at high risk for atherosclerosis. Hyperinsulinemia has been associated with proliferation, migration, and dedifferentiation of vascular smooth muscle cells (VSMCs) during the pathogenesis of atherosclerosis. Moreover, insulin-like growth factor-1 receptor (IGF-1R) and mammalian target of rapamycin (mTOR) have been demonstrated to be the underlying signaling pathways. Recently, microRNA-99a (miR-99a) has been suggested to regulate the phenotypic changes of VSMCs in cancer cells. However, whether it is involved in insulin-induced changes of VSCMs has not been determined. In this study, we found that insulin induced proliferation, migration, and dedifferentiation of mouse VSMCs in a dose-dependent manner. Furthermore, the stimulating effects of high-dose insulin on proliferation, migration, and dedifferentiation of mouse VSMCs were found to be associated with the attenuation of the inhibitory effects of miR-99a on IGF-1R and mTOR signaling activities. Finally, we found that the inducing effect of high-dose insulin on proliferation, migration, and dedifferentiation of VSMCs was partially inhibited by an active mimic of miR-99a. Taken together, these results suggest that miR-99a plays a key regulatory role in the pathogenesis of insulin-induced proliferation, migration, and phenotype conversion of VSMCs at least partly via inhibition of IGF-1R and mTOR signaling. Our results provide evidence that miR-99a may be a novel target for the treatment of hyperinsulinemia-induced atherosclerosis.
Department of Postgraduate, Kunming Medical University, Yunnan, 650500, China; Department of Cardiology, Kunming General Hospital of Chengdu Military Area, China.
Zi-Wei
ZW
Zhang
Department of Cardiology, Kunming General Hospital of Chengdu Military Area, China.
Rui-Wei
RW
Guo
Department of Postgraduate, Kunming Medical University, Yunnan, 650500, China; Department of Cardiology, Kunming General Hospital of Chengdu Military Area, China.
Jin-Lin
JL
Lv
Department of Cardiology, Kunming General Hospital of Chengdu Military Area, China.
Xian-Mei
XM
Wang
Department of Cardiology, Kunming General Hospital of Chengdu Military Area, China.
Jin-Shan
JS
Ye
Department of Postgraduate, Kunming Medical University, Yunnan, 650500, China; Department of Cardiology, Kunming General Hospital of Chengdu Military Area, China.
Ni-Hong
NH
Lu
Department of Cardiology, Kunming General Hospital of Chengdu Military Area, China.
Xing
X
Liang
Department of Cardiology, Kunming General Hospital of Chengdu Military Area, China. Electronic address: doctorlxyang@126.com.
Li-Xia
LX
Yang
D000818:Animals; D054337:Cell Dedifferentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D018716:Molecular Mimicry; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009843:Oligoribonucleotides / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
D007328:Insulin; D035683:MicroRNAs; C573158:Mirn99 microRNA, mouse; D009843:Oligoribonucleotides; C546843:mTOR protein, mouse; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases
Differentiation; Insulin; Proliferation; Rapamycin resistance; Vascular smooth muscle cells; miR-99a