Dual Benefit of Reduced Cx43 on Atherosclerosis in LDL Receptor-Deficient Mice

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Abstract
Paracrine cell-to-cell interactions are crucial events during atherogenesis, however, little is known on the role of gap junctional communication during this process. We recently demonstrated increased expression of Cx43 in intimal smooth muscle cells and in a subset of endothelial cells covering the shoulder of atherosclerotic plaques. The purpose of this study was to examine the role of Cx43 in the development of atherosclerosis in vivo. Atherosclerosis-susceptible LDL receptor-deficient (LDLR−/−) mice were intercrossed with mice heterozygous for Cx43 (Cx43+/−mice). Male mice with normal (Cx43+/+LDLR−/−) or reduced (Cx43+/−LDLR−/−) Cx43 level of 10 weeks old were fed a cholesterol-rich diet (1.25%) for 14 weeks. Both groups of mice showed similar increases in serum lipids and body weight. Interestingly, the progression of atherosclerosis was reduced by 50% (P < 0.01) in the thoraco-abdominal aorta and in the aortic roots of Cx43+/−LDLR−/−mice compared with Cx43+/+LDLR−/−littermate controls. In addition, atheroma in Cx43+/−LDLR−/−mice contained fewer inflammatory cells and exhibited thicker fibrous caps with more collagen and smooth muscle cells, important features associated, in human, with stable atherosclerotic lesions. Thus, reducing Cx43 expression in mice provides beneficial effects on both the progression and composition of the atherosclerotic lesions.