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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1391.)
© 2003 American Heart Association, Inc.

Vascular Biology

Reduced Expression of Endothelial Connexin37 and Connexin40 in Hyperlipidemic Mice

Recovery of Connexin37 After 7-Day Simvastatin Treatment

Hung-I Yeh; Chi-Sheng Lu; Yih-Jer Wu; Chih-Chun Chen; Ray-Ching Hong; Yu-Shien Ko; Ming-Shi Shiao; Nicholas J. Severs; Cheng-Ho Tsai

From Mackay Memorial Hospital (H.-I.Y., C.-S.L., Y.-J.W., C.-C.C., R.-C.H., C.-H.T.), Mackay Junior College of Nursing, Taipei Medical University, Taipei; the First Cardiovascular Division (Y.-S.K.), Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei; and the Department of Medical Research Education (M.-S.S.), Veterans General Hospital, Taipei, Taiwan; and the National Heart and Lung Institute (N.J.S.), Imperial College, London, England.

Correspondence to Cheng-Ho Tsai, Cardiac Medicine, Mackay Memorial Hospital, 92, Sec 2, North Chung San Rd, Taipei 10449, Taiwan. E-mail cht7678{at}ms2.mmh.org.tw

Objective— We sought to clarify the response of endothelial connexins to hyperlipidemia and lipid-lowering therapy.

Methods and Results— Aortic endothelial gap junctions were analyzed by en face immunoconfocal microscopy and electron microscopy in C57BL/6 mice subjected to the following regimens: (1) normal chow (NC) for 3 months (3 mo), (2) NC for 9 mo, (3) NC for 3 mo, followed by a cholesterol-enriched diet (CED) for 6 mo, (4) NC for 3 mo and CED for 6 mo, with simvastatin in the final week, and (5) (in apoprotein E [apoE]-deficient mice) NC and examined at 3 mo and 7 to 9 mo. In wild-type mice, connexin37 (Cx37) and Cx40 were markedly downregulated in the CED-fed animals compared with those fed NC (CED vs 9-mo NC, 77% reduction in Cx37 and 65% reduction in Cx40; both P<0.01). After simvastatin treatment, Cx40 remained depressed, but Cx37 recovered to 94% of the level found in non–cholesterol-fed animals (P<0.01). Electron microscopy demonstrated that gap junctions were smaller in animals fed the CED compared with those given simvastatin and with controls fed NC (P<0.01). Endothelial connexins were rare in the atherosclerotic plaques of apoE-deficient mice.

Conclusions— Mouse aortic endothelial gap junctions and connexins are downregulated during long-term hyperlipidemia. Short-term treatment with simvastatin leads to recovery of Cx37 expression but not Cx40 expression.

Key Words: gap junctions • connexins • endothelial cells • hyperlipidemia • simvastatin

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