Connexin37 protects against atherosclerosis by regulating monocyte adhesion

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Genetics

Background:

• A genetic polymorphism in human connexin37 (CX37) is a potential prognostic marker for atherosclerosis.
• CX37 expression is altered in atherosclerotic lesions, decreasing in endothelium and increasing in macrophages.
• The specific role of CX37 in atherogenesis is currently unknown.

Purpose of the Study:

• To investigate the effect of deleting the mouse connexin37 (Cx37) gene on atherosclerosis development.
• To determine whether Cx37 expression in leukocytes or endothelium is critical for its role in atherogenesis.
• To elucidate the mechanism by which CX37 influences monocyte adhesion and atherosclerotic plaque initiation.

Main Methods:

• Generated and studied atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) mice lacking the Cx37 gene (Gja4(-/-)Apoe(-/-)).
• Utilized in vivo adoptive transfer to assess the role of Cx37 in leukocyte and endothelial cells.
• Examined Cx37 hemichannel activity and ATP release in primary monocytes, macrophages, and a macrophage cell line (H36.12j).

Main Results:

• Gja4(-/-)Apoe(-/-) mice exhibited significantly more aortic lesions compared to Gja4(+/+)Apoe(-/-) mice.
• Eliminating Cx37 expression in monocytes and macrophages, but not in endothelium, enhanced leukocyte recruitment.
• Cx37 hemichannel activity inhibited leukocyte adhesion, mediated by extracellular ATP release.
• Macrophages expressing human CX37 variants showed differential ATP-dependent adhesion.

Conclusions:

• Loss of Cx37 exacerbates atherosclerosis in Apoe(-/-) mice, primarily by enhancing monocyte/macrophage recruitment.
• Cx37 hemichannels on leukocytes, through ATP release, play a crucial role in inhibiting leukocyte adhesion.
• These findings suggest Cx37 hemichannels regulate atherosclerotic plaque initiation and provide a mechanism for Cx37 polymorphism's protective effect.