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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 atherosclerosis1. The expression of this gap-junction protein is altered in mouse and human atherosclerotic lesions2: 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 disease3. 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.

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Figure 1: Deletion of Cx37 accelerates atherosclerosis in Apoe−/− mice.
Figure 2: Cx37 hemichannel activity regulates adhesion of macrophages and monocytes.
Figure 3: Cx37-dependent release of ATP regulates adhesion of macrophages and monocytes.
Figure 4: Polymorphic CX37 differentially regulates macrophage adhesion.

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Acknowledgements

We thank E. Sutter, T. Dudez, I. Scerri and A. Angelillo-Scherrer for technical assistance and discussions. This work was supported by grants from the Swiss National Science Foundation (SNSF; PPOOA-68883 and 3100-067777), the Swiss University Conference Program 'Heart Remodeling in Health and Disease', the Novartis Foundation and the Roche Research Foundation (to B.R.K.); the SNSF (310000-107846/1 to M.C.); and the National Institutes of Health (GM18974 to D.A.G.).

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Correspondence to Brenda R Kwak.

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Supplementary Fig. 1

Deletion of Cx37 enhances the transendothelial migration of macrophages. (PDF 1141 kb)

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Wong, C., Christen, T., Roth, I. et al. Connexin37 protects against atherosclerosis by regulating monocyte adhesion. Nat Med 12, 950–954 (2006). https://doi.org/10.1038/nm1441

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