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      Association of Connexin 37 Gene Polymorphisms with Risk of Coronary Artery Disease in Northern Han Chinese

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          Abstract

          Background: Recently, the C1019T polymorphism in the human gene encoding connexin 37 (CX37, encoded by GJA4) has been reported to be associated with coronary artery disease (CAD)/myocardial infarction in different racial groups, but no data are currently available in northern Han Chinese. The aim of our study is to investigate the association between 3 GJA4 gene polymorphisms (–1930C/T, C1019T and I1297D) and the susceptibility to CAD in northern Han Chinese. Methods: 502 CAD patients and 410 controls confirmed by coronary angiography were genotyped by polymerase chain reaction restriction fragment length polymorphism analysis in an independent case-control study. Results: The overall distribution of GJA4 C1019T genotypes among CAD patients and healthy controls was significantly different (p < 0.01). Frequencies of C1019T CC homozygote and C allele were significantly higher in the patient group than those in the control group. Stratification analysis showed that the C1019T C allele significantly increased the risk of CAD only among male subjects (p = 0.006; OR 1.38; 95% CI 1.09–1.74). After adjustment for conventional risk factors, binary logistic regression analysis showed that the C allele carrier (CC + CT) of C1019T was an independent risk factor for CAD (p < 0.05). Further linkage disequilibrium tests and haplotype analysis revealed that the C-C-D haplotype conferred an increased risk of CAD. Conclusions: Our study suggests that GJA4 gene C1019T polymorphism and/or its related C-C-D haplotype might contribute to an increased risk of CAD and potentially play an important role in the development of coronary atherosclerosis in northern Han Chinese.

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          Most cited references 15

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          Alterations of left ventricular myocardial characteristics associated with obesity.

          Obesity is associated with heart failure, but an effect of weight, independent of comorbidities, on cardiac structure and function is not well established. We sought whether body mass index (BMI) and insulin levels were associated with subclinical myocardial disturbances. Transthoracic echocardiography, myocardial Doppler-derived systolic (sm) and early diastolic velocity (em), strain and strain rate imaging and tissue characterization with cyclic variation (CVIB), and calibrated integrated backscatter (cIB) were obtained in 109 overweight or obese subjects and 33 referents (BMI 35) had reduced LV systolic and diastolic function and increased myocardial reflectivity compared with referents, evidenced by lower average long-axis strain, sm, cIB, lower CVIB, and reduced em, whereas LV ejection fraction remained normal. Differences in regional or global strain, sm, and em were identified between the severely obese (BMI >35) and the referent patients (P<0.001). Similar but lesser degrees of reduced function by sm, em, and basal septal strain and increased reflectivity by cIB were present in overweight (BMI, 25 to 29.9) and mildly obese (BMI, 30 to 35) groups (P<0.05). Although tissue Doppler measures were not associated with duration of obesity, they did correlate with fasting insulin levels and reduced exercise capacity. BMI was independently related to average LV strain (beta=0.40, P=0.02), sm (beta=-0.36, P=0.002), and em (beta=-0.41, P<0.001). Overweight subjects without overt heart disease have subclinical changes of LV structure and function even after adjustment for mean arterial pressure, age, gender, and LV mass.
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            Connexin37 protects against atherosclerosis by regulating monocyte adhesion.

            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.
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              Altered pattern of vascular connexin expression in atherosclerotic plaques.

              Paracrine cell-to-cell interactions are crucial events during atherogenesis. However, little is known about the role of direct intercellular communication via gap junctions during this process. We have investigated the expression pattern of 3 vascular gap junction proteins (connexins) in mouse and human atherosclerotic plaques. Low density lipoprotein receptor-deficient mice were fed a high-fat diet for 0, 6, 10, or 14 weeks to induce different stages of atherosclerosis. Connexin37 (Cx37) and Cx40 were detected in the endothelium, and Cx43 was detected in the media of nondiseased aortas. In early atheromas, endothelial and medial connexin expression remained unchanged, and "islets" of Cx43 in smooth muscle cells and Cx37 in macrophages were observed in the neointima. In advanced atheromas, Cx37 was detected in medial smooth muscle cells and in macrophages in the lipid core but not in the endothelium covering the plaques. Cx40 could also no longer be detected in the endothelium covering the plaques. Cx43, on the other hand, was detected in the endothelium covering the shoulder of the plaques and also sparsely in neointimal smooth muscle cells. Similar results were obtained for human carotid arteries. In conclusion, vascular connexins are differentially expressed by atheroma-associated cells within lesions. These observations suggest a role for gap junctional intercellular communication during atherogenesis.
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2008
                June 2008
                12 December 2007
                : 110
                : 4
                : 260-265
                Affiliations
                Department of Cardiology, Cardiovascular Research Institute, Northern Hospital, Shenyang, China
                Article
                112410 Cardiology 2008;110:260–265
                10.1159/000112410
                18073482
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Tables: 6, References: 23, Pages: 6
                Categories
                Original Research

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