title: Diabetes reduces aortic endothelial gap junctions in ApoE-deficient mice: simvastatin exacerbates the reduction.
abstract: We examined the endothelial gap junctions in diabetic hyperlipidemic mice. Male apolipoprotein E (apoE)-deficient mice were made diabetic by streptozotocin. Three weeks later, the animals were treated with simvastatin for 2 weeks. The expression of aortic gap junctions in the non-diabetic (n=10), untreated diabetic (n=10), and simvastatin-treated diabetic animals (n=6) was analyzed. There was a >4-fold increase in serum cholesterol level and >50% increase in plaque areas in the diabetic mice, regardless of simvastatin treatment. Western blotting of aortae showed reduced expression of connexin37 (Cx37) and Cx40 in the diabetic mice, which were further decreased in the simvastatin-treated diabetic mice. Immunoconfocal microscopy showed that endothelial gap junctions made of Cx37 and Cx40 were both reduced in the untreated diabetic mice compared with the non-diabetic mice (decrease: Cx37, 41%; Cx40, 42%; both p<0.01). The reduction was greater in the simvastatin-treated mice (decrease in treated diabetic vs non-diabetic: Cx37, 61%; Cx40, 79%; both p<0.01; decrease in treated diabetic vs untreated diabetic: Cx37, 34%; Cx40, 63%; both p<0.01). Cx37 and Cx40 were decreased in the endothelium of plaque surface. Cx43 appeared in the medial layer and inner layer of the intima. All three connexins were rarely expressed in monocytes/macrophages inside the plaques. In conclusion, in apoE-deficient mice, streptozotocin-induced diabetes is associated with downregulation of endothelial Cx37 and Cx40 gap junctions. Short-term treatment with simvastatin exacerbates the downregulation.
authors.affiliation: Department of Internal Medicine, Mackay Memorial Hospital, Mackay Medicine, Nursing and Management Collegem, Taipei, Taiwan.
authors.forename: Charles Jia-Yin
authors.initials: CJ
authors.lastname: Hou
authors.forename: Cheng-Ho
authors.initials: CH
authors.lastname: Tsai
authors.forename: Cheng-Huang
authors.initials: CH
authors.lastname: Su
authors.forename: Yih-Jer
authors.initials: YJ
authors.lastname: Wu
authors.forename: Su-Jen
authors.initials: SJ
authors.lastname: Chen
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Chiu
authors.forename: Ming-Shi
authors.initials: MS
authors.lastname: Shiao
authors.forename: Hung-I
authors.initials: HI
authors.lastname: Yeh
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D017630:Connexins / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D019821:Simvastatin / Q000494:pharmacology*; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein
chemical_list: D001057:Apolipoproteins E; D017630:Connexins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein