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Diabetes Reduces Aortic Endothelial Gap Junctions in ApoE-deficient Mice: Simvastatin Exacerbates the Reduction

Charles Jia-Yin Hou, Cheng-Ho Tsai, Cheng-Huang Su, Yih-Jer Wu, Su-Jen Chen, Jing-Jing Chiu, Ming-Shi Shiao and Hung-I Yeh

Departments of Internal Medicine and Medical Research, Mackay Memorial Hospital, Mackay Medicine, Nursing and Management College, Taipei, Taiwan (CJ-YH,C-HT,C-HS,Y-JW,S-JC,H-IY); Taipei Medical University, Taipei, Taiwan (C-HT,H-IY); and Department of Life Science, Chang Gung University, Tao-Yuan, Taiwan (J-JC,M-SS)

Correspondence to: Hung-I Yeh, Internal Medicine, Mackay Memorial Hospital, Sec 2, Chung San North Road, Taipei 10449, Taiwan. E-mail: hiyeh{at}ms1.mmh.org.tw

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. (J Histochem Cytochem 56:745–752, 2008)

Key Words: gap junction • endothelial cells • diabetes • hyperlipidemia • simvastatin

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