title: Diabetes and hyperlipidemia induce dysfunction of VSMCs: contribution of the metabolic inflammation/miRNA pathway.
abstract: Vascular endothelial cell injury is considered to be the major factor inducing vascular complications in metabolic diseases and plays an important role in other organ damage. With diabetic and hyperlipidemic rats and cultured VSMCs, the present study was aimed at investigating whether the early damage of VSMCs during metabolic diseases plays a critical role in vascular dysfunction and the underlying mechanisms and would be a promising treatment target. With diabetic and hyperlipidemic rats and cultured VSMCs, the changes and relationships of vascular relaxation and contractile function to the vital organ damage and the underlying mechanisms were investigated; meanwhile, the protective and preventive effects of lowering blood lipid and glucose and inhibition of diabetes and hyperlipidemia-induced vascular hyperreactivity were observed. Diabetic and hyperlipidemic rats presented hyperreactivity in vascular contractile response in the early stages. Hyperglycemia and hyperlipidemia directly affected the contractile function of VSMCs. Early application of fasudil, a specific antagonist of Rho kinase, significantly alleviated diabetes and hyperlipidemia-induced organ damage by inhibiting vascular hyperreactivity. Diabetes and hyperlipidemia-induced inflammatory response could upregulate the expression of connexins and Rho kinase by selective downregulation of the expression of miR-10a, miR-139b, miR-206, and miR-222. These findings suggest that hyperglucose and lipid may directly impair VSMCs and induce vascular hyperreactivity in the early stages. Metabolic inflammation-induced changes in the miRNA-connexin/Rho kinase regulatory pathway are the main mechanism for vascular hyperreactivity and organ damage. Measures inhibiting vascular hyperreactivity are promising for the prevention of organ damage induced by metabolic diseases.
authors.affiliation: State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Guang-ming
authors.initials: GM
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiang-yun
authors.initials: XY
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Lan
authors.affiliation: State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Kun-lun
authors.initials: KL
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China liangmingliu@yahoo.com.
authors.forename: Liang-ming
authors.initials: LM
authors.lastname: Liu
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003925:Diabetic Angiopathies / Q000209:etiology / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000517:prevention & control; D004359:Drug Therapy, Combination; D005260:Female; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D035683:MicroRNAs / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019821:Simvastatin / Q000627:therapeutic use; D014657:Vasculitis / Q000150:complications / Q000209:etiology / Q000517:prevention & control*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D017630:Connexins; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D008687:Metformin; D019821:Simvastatin; D054460:rho-Associated Kinases; C049347:fasudil
keywords: Rho kinase; metabolic disease; microRNA; vascular contraction; vascular smooth muscle cells