Health  Vol.2 No.3 , March 2010
Higher expression of connexin 40 in human atrial tissue of patients with type 2 diabetes who have undergone a coronary artery bypass graft surgery
Abstract: Background: Although cardiac-related mortality rates are declining for the general population in the United States, this is not the case for patients with diabetes. Diabetes is a significant independent predictor of atrial fibrillation (AF), the most common cardiac rhythm disturbance responsible for substantial morbidity and mortality. Objectives: This research was designed to evaluate properties of the atrial tissue between patients with and without type 2 diabetes. Heart rate variability (HRV) indices were calculated and expression of Kv1.5, connexin 43 (Cx43), and 40 (Cx40) were compared. Methods: Patients undergoing a CABG were enrolled: 10 with type 2 diabetes and 8 without diabetes, paired for age, gender and co-morbidities such as hypertension and dyslipidemia. All patients showed normal ejection fraction. A sample of right auricular appendix was taken during CABG and Kv1.5, Cx40 and Cx43 protein contents were determined by western blotting and normalized to α-tubulin level. Results: No HRV difference was found between patients with and without diabetes. Cx43 and Kv1.5 levels were unaffected by diabetes (p=0.20 and 0.07, respectively) whe- reas Cx40 content was significantly increased by 55% (p=0.02). Levels of Cx43 phosphorylated and non-phosphorylated forms were non-significantly decreased in patients with diabetes. Conclusion: Patients with type 2 diabetes had higher expression of Cx40 in the right auricular appendix tissue. In light of other studies having demonstrated a link between AF and Cx40 expression, it is possible that higher prevalence of AF in patients with diabetes is explained, at least partially, by differential expression of gap-junction proteins.
Cite this paper: nullDaleau, P. , Comeau, G. , Fournier, D. , Patoine, D. , Mathieu, P. and Poirier, P. (2010) Higher expression of connexin 40 in human atrial tissue of patients with type 2 diabetes who have undergone a coronary artery bypass graft surgery. Health, 2, 272-278. doi: 10.4236/health.2010.23039.

[1]   Gu, K., Cowie, C.C. and Harris, M.I. (1999) Diabetes and decline in heart disease mortality in US adults. Journal of the American Medical association, 281, 1291- 1297.

[2]   Grundy, S.M., Benjamin, I.J., Burke, G.L., Chait, A., Eckel, R.H., Howard, B.V., Mitch, W., Smith, S.C.Jr. and Sowers, J.R. (1999) Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation, 100, 1134- 1146.

[3]   Fuster, V., Ryden, L.E., Cannom, D.S., Crijns, H.J., Curtis, A.B., Ellenbogen, K.A., Halperin, J.L., Le Heuzey, J.-Y., Kay, G.N., Lowe, J.E., Olsson, S.B., Prystowsky, E.N., Tamargo, J.L. and Wann, S. (2006) ACC/AHA Task Force Members, ESC Committee for Practice Guidelines: ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Comm

[4]   Benjamin, E.J., Levy, D., Vaziri, S.M., D'Agostino, R.B., Belanger, A.J. and Wolf, P.A. (1994) Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. Journal of the American Medical association, 271, 1-11.

[5]   Allessie, M.A., Boyden, P.A., Camm, A.J., Kléber, A.G., Lab, M.J., Legato, M.J., Rosen, M.R., Schwartz, P.J., Spooner, P.M., Van Wagoner, D.R. and Waldo, A.L. (2001) Pathophysiology and prevention of atrial fibrillation. Circulation, 103, 769-777.

[6]   Poirier, P., Bogaty, P., Garneau, C., Marois, L. and Dumesnil, J.G. (2001) Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. Diabetes Care, 24, 5-10.

[7]   Poirier, P., Bogaty, P., Philippon, F., Garneau, C., Fortin, C. and Dumesnil, J.G. (2003) Preclinical diabetic cardiomyopathy: relation of left ventricular diastolic dysfunction to cardiac autonomic neuropathy in men with uncomplicated well-controlled type 2 diabetes. Metabolism, 52, 1056-1061.

[8]   Magyar, J., Rusznak, Z., Szentesi, P., Szucs, G. and Kovacs, L. (1992) Action potentials and potassium currents in rat ventricular muscle during experimental diabetes. Journal of Molecular and Cellular Cardiology, 24, 841-853.

[9]   Nishiyama, A., Ishii, D.N., Backx,.P.H., Pulford, B.E., Birks, B.R. and Tamkun, M.M. (2001) Altered K+ channel gene expression in diabetic rat ventricle: isoform switching between Kv4.2 and Kv1.4. American Journal of Physiology, 281, H1800-H1807.

[10]   Gallego, M., Casis, E. and Izquierdo, M.J. (2000) Restoration of cardiac transient outward potassium current by norepinephrine in diabetic rats. Pflügers Archives, 441, 102-107.

[11]   Xu, Z., Patel, K., Lou, M.F. and Rozanski, G.J. (2002) Up-regulation of K+ channels in diabetic rat ventricular myocytes by insulin and glutathione. Cardiovascular Research, 53, 80-88.

[12]   Pacher, P., Ungvari, Z., Nanasi, P.P. and Kecskeméti, V. (1999) Electrophysiological changes in rat ventricular and atrial myocardium at different stages of experimental diabetes. Acta Physiologica Scandinavica, 166, 7-13.

[13]   Yang, Q., Kiyoshige, K., Fujimoto, T., Katayama, M., Fujino, K., Saito, K., Nakaya, Y. and Mori, H. (1990) Signal-averaging electrocardiogram in patients with diabetes mellitus. Japanese Heart Journal, 31, 25-33.

[14]   Celiker, A., Akinci, A. and ?zin, B. (1994) The signal-averaged electrocardiogram in diabetic children. International Journal of Cardiology, 44, 271-274.

[15]   Inoguchi, T., Ueda, F., Umeda, F., Yamashita, T. and Nawata, H. (1995) Inhibition of intercellular communication via gap junction in cultured aortic endothelial cells by elevated glucose and phorbol ester. Biochemical and Biophysical Research Communications, 208, 492-497.

[16]   Kuroki, T., Inoguchi, T., Umeda, F., Ueda, F. and Nawata, H. (1998) High glucose induces alteration of gap junction permeability and phosphorylation of connexin-43 in cultured aortic smooth muscle cells. Diabetes, 47, 931-936.

[17]   Inoguchi, T., Yu, H.Y., Imamura, M., Kakimoto, M., Kuroki, T., Maruyama, T. and Nawata, H. (2001) Altered gap junction activity in cardiovascular tissues of diabetes. Medical Electron Microscopy, 34, 86-91.

[18]   Oku, H., Kodama, T., Sakagami, K., Puro, D.G. (2001) Diabetes-induced disruption of gap junction pathways within the retinal microvasculature. Investigative Ophthalmology and Visual Science, 42, 1915-1920.

[19]   Poladia, D.P., Schanbacher, B., Wallace, L.J. and Bauer, J.A. (2005) Innervation and connexin isoform expression during diabetes-related bladder dysfunction: early structural vs. neuronal remodeling. Acta Diabetologica, 42, 147-152.

[20]   Stilli, D, Lagrasta, C., Berni, R., Bocchi, L., Savi, M., Delucchi, F., Graiani, G., Monica, M., Maestri, R., Baruffi, S., Rossi, S., Macchi, E., Musso, E. and Quaini, F. (2007) Preservation of ventricular performance at early stages of diabetic cardiomyopathy involves changes in myocyte size, number and intercellular coupling. Basic Research in Cardiology, 102, 488-499.

[21]   Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology: Heart rate variability (1996) Standards of measurement, physiological interpretation, and clinical use. European Heart Journal, 17, 354-381.

[22]   Daleau, P., Boudriau, S., Michaud, M., Jolicoeur, C. and Kingma, J.G. Jr. (2001) Preconditioning in the absence or presence of sustained ischemia modulates myocardial Cx43 protein levels and gap junction distribution. Canadian Journal of Physiology and Pharmacology, 79, 371- 378.

[23]   Sarrazin, J.-F., Comeau, G., Daleau, P., Kingma, J., Plante, I., Fournier, D. and Molin, F. (2007) Reduced incidence of vagally-induced atrial fibrillation and expression levels of connexins by n-3 polyunsaturated fatty acids in dogs. Journal of the American College of Cardiology, 50, 1505-1512.

[24]   Lin, H., Ogawa, K., Imanaga, I. and Tribulova, N. (2006) Alterations of connexin 43 in the diabetic rat heart. Advance in Cardiology, 42, 243-254.

[25]   Okruhlicova, L., Tribulova, N., Misejkova, M., Kucka, M., Stetka, R., Slezak, J. and Manoach, M. (2002) Gap junction remodeling is involved in the susceptibility of diabetic rats to hypokalemia-induced ventricular fibrillation. Acta Histochemica, 104, 387-391.

[26]   Sheu, J.-J., Chang, L.-T., Chiang, C.-H., Sun, C.-K., Chang, N.-K., Youssef, A.A., Wu, C.-J., Lee, F.-Y. and Yip, H.-K. (2007) Impact of diabetes on cardiomyocyte apoptosis and connexin43 gap junction integrity. Role of pharmacological modulation. International Heart Journal, 48, 233-245.

[27]   Brink, P.R., Valiunas, V., Wang, H.Z., Zhao, W., Davies, K. and Christ, G.J. (2006) Experimental diabetes alters connexin43 derived gap junction permeability in short- term cultures of rat corporeal vascular smooth muscle cells. Journal of Urology, 175, 381-386.

[28]   Howarth, F., Nowotny, N., Zilahi, E., El Haj, M. and Lei, M. (2007) Altered expression of gap junction connexin proteins may partly underlie heart rhythm disturbances in the streptozotocin-induced diabetic rat heart. Molecular and Cellular Biochemistry, 305, 145-151.

[29]   Wolfle, S.E., Schmidt, V.J., Hoepfl, B., Gebert, A., Alcolea, S., Gros, D. and de Wit, C. (2007) Connexin45 cannot replace the function of connexin40 in conducting endothelium-dependent dilations along arterioles. Circulation Research, 101, 1292-1299.

[30]   ?stgren, C.J., Merlo, J., R?stam, L. and Lindblad, U. (2004) Atrial fibrillation and its association with type 2 diabetes and hypertension in a Swedish community. Diabetes, Obesity and Metabolism, 6, 367-374.

[31]   Movahed, M.-R., Hashemzadeh, M. and Jamal, M.M. (2005) Diabetes mellitus is a strong, independent risk for atrial fibrillation and flutter in addition to other cardiovascular disease. International Journal of Cardiology, 105, 315-318.

[32]   Dupont, E., Ko, Y.-S., Rothery, S., Coppen, S.R., Baghai, M., Haw, M. and Severs, N.J. (2001) The gap-junctional protein connexin 40 is elevated in patients susceptible to postoperative atrial fibrillation. Circulation, 103, 842- 849.

[33]   Polontchouk, L., Haefliger, J.-A., Ebelt, B., Schaefer, T., Stuhlmann, D., Mehlhorn, U. and Kuhn-Regnier, F. (2001) Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria. Journal of the American College of Cardiology, 38, 883-891.

[34]   Kostin, S., Klein, G., Szalay, Z., Hein, S., Bauer, E.P. and Schaper, J. (2002) Structural correlate of an atrial fibrillation in human patients. Cardiovascular Research, 54, 361-379.

[35]   Wetzel, U., Boldt, A., Lauschke, J., Weigl, J., Schirdewahn, P., Dorszewski, A., Doll, N., Hindricks, G., Dhein, S. and Kottkamp, H. (2005) Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies. Heart, 91, 166-170.

[36]   Beauchamp, P., Yamada, K.A., Baertschi, A.J., Green, K., Kanter, E.M., Saffitz, J.E. and Kléber, A.G. (2006) Relative contributions of connexins 40 and 43 to atrial impulse propagation in synthetic strands of neonatal and fetal murine cardiomyocytes. Circulation Research, 99, 1216-1224.

[37]   Zhang, Y., Xiao, J., Lin, H., Luo, X., Wang, H., Bai, Y., Wang, J., Zhang, H., Yang, B. and Wang, Z. (2007) Ionic mechanisms underlying abnormal QT prolongation and the associated arrhythmias in diabetic rabbits: a role of rapid delayed rectifier K+ current. Cellular Physiology and Biochemistry, 19, 225-238.

[38]   Lengyel, C., Virag, L., Biro, T., Jost, N., Magyar, J., Biliczki, P., Kocsis, E., Skoumal, R., Nanasi, P.P., Toth, M., Kecskemeti, V., Papp, J.G. and Varro, A. (2007) Diabetes mellitus attenuates the repolarization reserve in mammalian heart. Cardiovascular Research, 73, 512- 520.

[39]   Casis, O., Gallego, M., Iriarte, M. and Sanchez-Chapula, J.A. (2000) Effects of diabetic cardiomyopathy on regional electrophysiologic characteristics of rat ventricle. Diabetologia, 43, 101-109.

[40]   Fernandez-Cobo, M., Gingalewski, C., Drujan, D. and De Maio, A. (1999) Downregulation of connexin 43 gene expression in rat heart during inflammation. The role of tumour necrosis factor. Cytokine, 11, 216-224.

[41]   Fukuda, T., Ikejima, K., Hirose, M., Takei, Y., Watanabe, S. and Sato, N. (2000) Taurine preserves gap junctional intercellular communication in rat hepatocytes under oxidative stress. Journal of Gastroenterology, 35, 361- 368.