Diabetes Reduces Aortic Endothelial Gap Junctions in ApoE-deficient Mice: Simvastatin Exacerbates the Reduction
Charles Jia-Yin Hou 1, Cheng-Ho Tsai 1, Cheng-Huang Su 1, Yih-Jer Wu 1, Su-Jen Chen 1, Jing-Jing Chiu 1, Ming-Shi Shiao 1 and Hung-I Yeh 1*
1 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)
* To whom correspondence should be addressed. E-mail: hiyeh{at}ms1.mmh.org.tw.
Submitted on January 23, 2008
Accepted on 15 April 2008
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Abstract |
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We examined the endothelial gap junctions in diabetic hyperlipidemic mice. Male 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) were 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 to the non-diabetic (decrement, Cx37, 41%; Cx40, 42%; both p<0.01). The reduction was greater in the simvastatin-treated mice (decrement, treated diabetic vs non-diabetic, Cx37, 61%; Cx40, 79%; both p<0.01; treated diabetic vs untreated diabetic, Cx37, 34%; Cx40, 63%; both p<0.01). Cx37 and Cx40 were less in the endothelium of plaque surface. Cx43 appeared in the medial layer as well as inner layer of the intima. All 3 connexins were rarely expressed in monocytes/macrophages inside the plaques. In conclusion, in apoE-deficient mice streptozotocin-induced diabetes is associated with down-regulation of endothelial Cx37 and Cx40 gap junctions. Short-term treatment with simvastatin exacerbates the down-regulation.
Key Words:
gap junction, endothelial cells, diabetes, hyperlipidemia, simvastatin
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