Upregulation of Connexin43 Gap Junctions During Early Stages of Human Coronary Atherosclerosis

Abstract

Interactions between cells form the framework for understanding the pathogenesis of atherosclerosis, but little information is available on the role of direct intercellular communication via gap junctions in this process. To investigate gap junction expression in the pathogenesis of human atherosclerosis, lesions representing different stages of the disease were obtained from coronary arteries of hearts removed from patients undergoing cardiac transplantation. Twelve hearts, each providing 1 to 3 segments of artery, were used in the study. Sections were examined by confocal laser scanning microscopy after immunofluorescent labeling with a specific antibody against connexin43, the major gap-junctional protein of smooth muscle cells, to permit high-definition visualization of immunolabeled gap junctions through the depth of the specimen. Double labeling using anti-connexin43 and cell type-specific antibodies demonstrated colocalization of gap junctions with smooth muscle cells but not with macrophages, a relationship confirmed by electron microscopy. Regions of intimal thickening and early atheromatous lesions showed markedly increased expression of connexin43 gap junctions between intimal smooth muscle cells compared with the undiseased vessels. This increase in gap junctions was most marked in regions of intimal thickening, semiquantitative analysis of the confocal digital images revealing a > 10-fold increase compared with the undiseased vessel. The quantity of labeled gap junctions in early atheromatous lesions, although higher than that of the undiseased vessel, was lower than that of intimal thickenings, and this trend toward reduced levels of gap junction immunolabeling with lesion progression continued, the value observed in the most advanced atheromatous lesions being lower than that of the undiseased vessel. As the quantity of gap junctions declined, their distribution became more patchy and the sizes of individual junctions larger. The results suggest that enhanced expression of gap junctions between smooth muscle cells may play a role in maintaining the synthetic phenotype during early growth of the atherosclerotic plaque.

Differential Expression of Connexin43 and Desmin Defines Two Subpopulations of Medial Smooth Muscle Cells in the Human Internal Mammary Artery

“…The present findings refine the view suggested from previous studies 2,3,18,19 that high levels of Cx43 expression are associated with SMCs of a less contractile and more synthetic state, typically in an environment rich in extracellular matrix. These observations suggest that Cx43 gapjunctional intercellular communication may somehow be linked to the ability of SMCs to coordinate synthesis of extracellular matrix components, maintain the functional integrity of elastic media and/or regulate the repair and formation of the intima in vascular injury and disease.…”

“…1 Recent evidence suggests that a further signaling mechanism, direct intercellular communication via gap junctions, may also participate in these interactions. 2,3 Gap junctions are clusters of transmembrane channels that link the cytoplasmic compartments of neighboring cells, allowing direct exchange of ions, second messengers, and small signaling molecules. The gap-junctional channel is constructed from a pair of hemichannels termed connexons, each connexon being assembled from 6 connexin molecules.…”

“…17 Recent evidence further suggests that increased Cx43-gap junction expression in arterial SMCs is intimately linked to transition to the synthetic phenotype, suggesting a possible role in regulation of extracellular matrix synthesis or other properties of the synthetic state cell. Cultured aortic SMCs express higher levels of immunodetectable Cx43 in the synthetic phenotype than in the contractile phenotype, 18 and abundant Cx43-gap junctions are formed between intimal SMCs during the early stages of human coronary atherosclerosis 2 and after balloon catheter injury in the rat carotid artery. 3 During the development of the rat aorta, Cx43 expression is low in the media before birth but starts to increase postnatally, coincident with thickening of the media and deposition of elastic laminae.…”

Effects of angiotensin II on connexin 43 of VSMCs in arteriosclerosis

“…It was formed that after the transformation of VSMC from differentiated contractile state to the activated synthetic state, the expression of Cx43 in VSMC increased sixfold and GJ diameter was enlarged (Inoguchi et al, 1995). Study showed that the expression of Cx43 at the thickened site of the endomembrane during early arteriosclerosis was highly elevated (Blackburn et al, 1995). Another study showed that Cx43 level is upregulated during the proliferation process of VSMC after the aorta was subjected to balloon injury or the animal was fed high-cholesterol diet (Polacek et al, 1997).…”

Genetic risk for myocardial infarction in Japanese individuals with or without chronic kidney disease

“…Sema domain, immunoglobulin domain, short basic domain, secreted, 3F (SEMA3F) is a member of the class 3 semaphorins and plays an important role in endothelial cell functions in vasculature (36). Inhibition of SEMA3F expression by small interfering RNA affected the intracellular localization and function of gap junction protein, ·1, 43 kDa which is expressed in medial smooth muscle cells of the normal vascular wall (37,38), being increased at early stages of atherosclerosis and reduced in advanced lesion (39).…”