Reduced Connexin43 Expression Inhibits Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor–Deficient Mice

Abstract

Background— Gap junctions allow the direct exchange of ions and small molecules between cells in contact, thus coordinating physiological processes such as cell growth and differentiation. We have recently demonstrated increased expression of the gap junction protein connexin43 (Cx43) in specific subsets of cells in atherosclerotic lesions. Because the development of atherosclerosis depends critically on paracrine cell-to-cell interactions, we hypothesized that direct intercellular communication via gap junctions may be another factor controlling atherogenesis. Methods and Results— The role of Cx43 in atherogenesis was examined by use of both a genetic and a pharmacological approach. First, atherosclerosis-susceptible LDL receptor–deficient (LDLR −/− ) mice with normal (Cx43 +/+ ) or reduced (Cx43 +/− ) levels of Cx43 were fed a cholesterol-rich diet for 14 weeks. The progression of atherosclerosis was reduced by 50% ( P <0.01) in the thoracoabdominal aorta and in the aortic roots of Cx43 +/− LDLR −/− mice compared with Cx43 +/+ LDLR −/− controls. Atheroma in Cx43 +/− LDLR −/− mice contained fewer inflammatory cells and exhibited thicker fibrous caps with more collagen and smooth muscle cells. Next, we observed that HMG-CoA reductase inhibitors, or “statins,” lipid-lowering drugs well known for their pleiotropic antiatherogenic effects, reduced Cx43 expression in primary human vascular cells in vitro. Atheroma of LDLR −/− mice treated orally with pravastatin contained fewer inflammatory cells and exhibited thicker fibrous caps than controls. This was associated with reduced Cx43 expression in lesions of statin-treated mice. Conclusions— These data indicate a critical role for Cx43-mediated gap junctional communication in atherosclerotic plaque formation.

WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication

“…28 It has previously been reported that connexin 43 expression is upregulated in smooth muscle cells in response to injury in rodent models and in early human atherosclerosis, situations in which elevated Wnt signaling has been reported 7,14 and in which increased extracellular matrix synthesis is well documented. 3,38 Reducing connexin 43 expression has been shown to inhibit lesion development in rodent models of atherosclerosis and acute vascular injury, [39][40][41] suggesting potential pro-atherogenic functions for gap junction communication. Our data suggest Wnt3a increases the expression of connexin 43 in vascular smooth muscle cells, and this increase in connexin 43 expression is associated with increased intercellular communication and matrix synthesis.…”

Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature

“…Boerma et al (39) identified a genetic polymorphism in Cx37 as a prognostic marker for atherosclerotic plaque development. Furthermore, reduced Cx43 expression inhibits atherosclerotic lesion formation in LDLRϪ͞Ϫ mice (40).…”

Effects of Losartan and Ramipril on the connexin expression in a rabbit balloon injury model

“…It is evident that the expressions of Cx40 and Cx43 are altered when the cultured SMCs transform from the contractile state to the synthetic state. Furthermore, experiment on the heterozygotic rat with congenital deficiency of Cx43 shows a decrease of atheromatous plaque by approximately 50% when compared with normal controls, indicating the Cx43 is essential for the atherosclerosis (Kwak et al, 2003). Accordingly, the role of GJ and connexins in the formation and growth of atheromatous plaque, and the restenosis following percutaneous transluminal coronary angioplasty (PTCA) has almost been clarified, and it is important to manipulate the function and regulation of GJ and connexins in order to reduce the occurrence of such lesions.…”