Connexin37 protects against atherosclerosis by regulating monocyte adhesion

Abstract

A genetic polymorphism in the human gene encoding connexin37 (CX37, encoded by GJA4, also known as CX37) has been reported as a potential prognostic marker for atherosclerosis. The expression of this gap-junction protein is altered in mouse and human atherosclerotic lesions: it disappears from the endothelium of advanced plaques but is detected in macrophages recruited to the lesions. The role of CX37 in atherogenesis, however, remains unknown. Here we have investigated the effect of deleting the mouse connexin37 (Cx37) gene (Gja4, also known as Cx37) on atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) mice, an animal model of this disease. We find that Gja4(-/-)Apoe(-/-) mice develop more aortic lesions than Gja4(+/+)Apoe(-/-) mice that express Cx37. Using in vivo adoptive transfer, we show that monocyte and macrophage recruitment is enhanced by eliminating expression of Cx37 in these leukocytes but not by eliminating its expression in the endothelium. We further show that Cx37 hemichannel activity in primary monocytes, macrophages and a macrophage cell line (H36.12j) inhibits leukocyte adhesion. This antiadhesive effect is mediated by release of ATP into the extracellular space. Thus, Cx37 hemichannels may control initiation of the development of atherosclerotic plaques by regulating monocyte adhesion. H36.12j macrophages expressing either of the two CX37 proteins encoded by a polymorphism in the human GJA4 gene show differential ATP-dependent adhesion. These results provide a potential mechanism by which a polymorphism in CX37 protects against atherosclerosis.

Inflammatory conditions induce gap junctional communication between rat Kupffer cells both in vivo and in vitro

“…Our in vivo and in vitro results indicate that KCs express at least Cx43 but they might also express other Cx types as other macrophagic cells do. For example, monocyte/ macrophages also express Cx37 (21) and Cx45 (19) and microglia also express Cx36 (22).…”

Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor

“…Moreover, a critical role for Cx43 has been reported in human saphenous vein during the development of intimal hyperplasia (Deglise et al 2005) and restenosis (Plenz et al 2004) and Cx43 decreases smooth muscle cell proliferation and limits neointima formation after vascular injury (Chadjichristos et al 2006). Conversely, regeneration of the endothelium following carotid artery injury in rats, a process essential for wound healing, is associated with increasing expression of Cx37, Cx40, and Cx43 (Yeh et al 2000).…”

“…more than one type of connexin) cell communication and, in particular, has been attributed to gap junctions comprised Cx40 and Cx37 (Zahler et al 2003) and Cx43 (Parthasarathi et al 2006). More recently, the functional consequences of this inhibitory activity have been highlighted in APOE KO mice (a model of atherosclerosis) also deleted for Cx37, where lesion formation was substantially enhanced (Wong et al 2006). Several studies clearly demonstrate that the expression of Cx37, Cx40, and Cx43 are all regulated by estrogen (Di et al 2001, Punyadeera et al 2005, and it is likely that this regulation, to some extent, underlies the effects of female sex hormones on leukocyte recruitment, such that the enhancement of expression of the gap junctions may in part mediate the decreased inflammatory cell recruitment evident in female animal models of inflammation.…”

Lack of association between the connexin 37 C1019T gene polymorphism and coronary artery disease in a Chinese population: Meta-analysis of 2,206 subjects

“…The cell gap junction is an important channel for message exchange between cells (20). In 2006, Wong et al found that Cx37 knockout mononuclear phagocytes adhered to the endothelium more strongly than Cx37-deficient cells (21). This characteristic was associated with the adenosine triphosphate (ATP) release between cells.…”