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Objectives: This study investigated the regulation of glucose uptake in cells that participate in atherogenesis by stimuli relevant to this process, to gain mechanistic insight into the origin of the (18)fluorine-labeled 2-deoxy-D-glucose (FdG) uptake signals observed clinically., Background: Patient studies suggest that positron emission tomography (PET) using FdG can detect "active" atherosclerotic plaques, yet the mechanism giving rise to FdG signals remains unknown., Methods: We exposed cells to conditions thought to operate in atheroma and determined rates of glucose uptake., Results: Hypoxia, but not pro-inflammatory cytokines, potently stimulated glucose uptake in human macrophages and foam cells. Statins attenuated this process in vitro, suggesting that these agents have a direct effect on human macrophages. Immunohistochemical study of human plaques revealed abundant expression of proteins regulating glucose utilization, predominantly in macrophage-rich regions of the plaques-regions previously proved hypoxic. Smooth-muscle cells and endothelial cells markedly increased rates of glucose uptake when exposed to pro-inflammatory cytokines., Conclusions: Glucose uptake and, probably, FdG uptake signals in atheroma may reflect hypoxia-stimulated macrophages rather than mere inflammatory burden. Cytokine-activated smooth-muscle cells also may contribute to the FdG signal., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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.

Aim Prostaglandin E2, by ligation of its receptor EP4, suppresses the production of inflammatory cytokines and chemokines in macrophages in vitro. Thus, activation of EP4 may constitute an endogenous anti-inflammatory pathway. This study investigated the role of EP4 in atherosclerosis in vivo, and particularly its impact on inflammation. Methods and results Ldlr−/− mice transplanted with EP4+/+ or EP4−/− bone marrow consumed a high-fat diet for 5 or 10 weeks. Allogenic bone marrow transplantation promoted exacerbation of atherosclerosis irrespective of EP4 genotype, compatible with prior observations of exacerbated atherogenesis by allogenicity. EP4 deficiency had little effect on plaque size or morphology in early atherosclerosis, but at the later time point, mice deficient in EP4 displayed enhanced inflammation in their atherosclerotic plaques. Expression of monocyte chemoattractant protein-1 and interferon-γ inducible protein 10 increased, and there was a corresponding increase in macrophage and T-cell infiltration. These plaques also contained fewer smooth muscle cells. Despite these changes, mice deficient in EP4 in bone marrow-derived cells at an advanced stage had similar lesion size (in both aorta and aortic root) as mice with EP4. Conclusion This study shows that in advanced atherosclerosis, EP4 deficiency did not alter atherosclerotic lesion size, but yielded plaques with exacerbated inflammation and altered lesion composition. [ABSTRACT FROM AUTHOR]

Abstract: A C1019T polymorphism in the human connexin37 (hCx37) gene has been associated with cardiovascular risk, but it remains debatable whether the 1019C or the 1019T allele carries this risk. Here, we investigated whether these allelic variants are differentially predictive of increased risk for coronary artery disease (CAD) and myocardial infarction (MI). A total of 781 Swiss participants, including 597 patients diagnosed with CAD, 50% who reported previous MI, and 184 control subjects were genotyped. Patients in the +CAD group had a higher frequency of the Cx37-1019C allele (70.3% versus 65.0%, p =0.004). Multivariate analysis showed that the hCx37-C1019T polymorphism is an independent predictor of CAD (odds ratio=2.13, confidence interval=1.31–3.46 and p <0.01). Moreover, this polymorphism is not associated with any of the other characteristics examined, including gender, age, body-mass-index, diabetes, total/HDL/LDL-cholesterol, triglycerides, apoA-I, apoB, hypertension and cigarette smoking. In comparison with the −CAD group, we observed an increase of the Cx37-1019C allele in the +MI +CAD subgroup (71.2% versus 65.0%, p =0.002) but not in the −MI +CAD subgroup. Allelic frequency comparisons of these three subgroups predicted that this polymorphism is also an independent risk factor for MI. In conclusion, our results reveal the importance of screening the Cx37-1019C allele for both CAD and MI risk assessments. [Copyright &y& Elsevier]

Gap junctions, formed by the connexin (Cx) protein family, are intercellular channels that permit the cytoplasmic exchange of ions and small metabolites between neighboring cells, a process called gap junction intercellular communication (GJIC). These channels possess unique properties, including distinctive permeabilities for various signaling molecules, which depend on the connexin member(s) that form them. Importantly, GJIC must be properly controlled as its misregulation might contribute to diseases. Morphological and functional studies have revealed ‘gap junction-like’ structures and cell-to-cell communication involving cells of the immune system. The connexins involved in such contacts have been partially identified in recent years. This review focuses on the potential physiological roles of gap junctions in the development and recruitment of leukocytes as well as in the regulation of the immune response. Furthermore, the importance of GJIC in immuno-inflammatory pathologies is illustrated in atherosclerosis. [Copyright &y& Elsevier]

Objectives: This study investigated the regulation of glucose uptake in cells that participate in atherogenesis by stimuli relevant to this process, to gain mechanistic insight into the origin of the 18fluorine-labeled 2-deoxy-D-glucose (FdG) uptake signals observed clinically. Background: Patient studies suggest that positron emission tomography (PET) using FdG can detect “active” atherosclerotic plaques, yet the mechanism giving rise to FdG signals remains unknown. Methods: We exposed cells to conditions thought to operate in atheroma and determined rates of glucose uptake. Results: Hypoxia, but not pro-inflammatory cytokines, potently stimulated glucose uptake in human macrophages and foam cells. Statins attenuated this process in vitro, suggesting that these agents have a direct effect on human macrophages. Immunohistochemical study of human plaques revealed abundant expression of proteins regulating glucose utilization, predominantly in macrophage-rich regions of the plaques—regions previously proved hypoxic. Smooth-muscle cells and endothelial cells markedly increased rates of glucose uptake when exposed to pro-inflammatory cytokines. Conclusions: Glucose uptake and, probably, FdG uptake signals in atheroma may reflect hypoxia-stimulated macrophages rather than mere inflammatory burden. Cytokine-activated smooth-muscle cells also may contribute to the FdG signal. [ABSTRACT FROM AUTHOR]