Molecular mechanisms of atherosclerosis: role of connexins

Atherosclerosis is an immuno-inflammatory disease of arteries, involving complex intercellular interactions. Direct communication through hemichannels and gap junction channels formed by connexins is important in atherosclerosis. This thesis first reviews the current knowledge on vascular connexins (Cx37, Cx40 and Cx43) in atherosclerosis. It then describes the association between connexin gene polymorphisms and coronary artery disease. Atherosclerosis localization being determined by flow patterns, this work then examines the interrelation between Cx37 and shear stress. High laminar shear stress upregulates endothelial Cx37 expression. Conversely, absence of Cx37 in mouse models of flow-dependent atherosclerosis alters plaque composition. Besides their role as (hemi)channel-forming proteins, connexins can also interact with other proteins. We unveil two interactions of Cx37: In endothelial cells, Cx37 interacts with eNOS, which is crucial for endothelial quiescence. In pDCs, Cx37 could interact with CIITA, which plays a central role in antigen presentation. Finally, these topics are integrated, and clinical implications of this work are discussed