PP  Vol.5 No.4 , April 2014
Pharmacological Effects of Statins Related to Gap Junction Modulation
Abstract: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or “statins”, are widely using cholesterol-lowering drugs with pleiotropic pharmacological effects. In this review, we summarized the pharmacological effects of statins related to gap junction modulation. The main function of cellular gap junctions, which are composed of trans-membrane proteins named connexins (Cxs), is to mediate direct cell-to-cell communication through material exchange. Statins could rectify the disturbed expression, distribution, or phosphorylation of Cxs and thus modify the functions of gap junctions in a variety of tissues like the aorta, cardiomyocytes, or tumors. The effects of statins on Cxs and gap junctions were associated with their pharmacological activities against atherosclerosis, arrhythmias, and tumors. Despite some evidences suggested that the anti-inflammatory or HMG-CoA reductase inhibiting effects of statins may contribute in part to the modulation of Cxs and gap junctions, the detailed underlying mechanisms are largely unrevealed and merit further investigation. In addition, it is likely that the modulating effects of statins on gap junctions may also contribute to their pharmacological activities against some diabetic complications. Future studies of these issues will help to provide scientific evidences for the appropriate clinical application of statins.
Cite this paper: Qu, L. , Jiang, J. and Kong, W. (2014) Pharmacological Effects of Statins Related to Gap Junction Modulation. Pharmacology & Pharmacy, 5, 319-331. doi: 10.4236/pp.2014.54039.

[1]   Brooke, M.A., Nitoiu, D. and Kelsell, D.P. (2012) Cell-Cell Connectivity: Desmosomes and Disease. The Journal of Pathology, 226, 158-171.

[2]   Nekrasova, O. and Green, K.J. (2013) Desmosome Assembly and Dynamics. Trends in Cell Biology, 23, 537-546.

[3]   Roberts, T.K., Eugenin, E.A., Lopez, L., Romero, I.A., Weksler, B.B., Couraud, P.O. and Berman, J.W. (2012) CCL2 Disrupts the Adherens Junction: Implications for Neuroinflammation. Laboratory Investigation, 92, 1213-1233.

[4]   Rodgers, L.S., Beam, M.T., Anderson, J.M. and Fanning, A.S. (2013) Epithelial Barrier Assembly Requires Coordinated Activity of Multiple Domains of the Tight Junction Protein ZO-1. Journal of Cell Science, 126, 1565-1575.

[5]   Mese, G., Richard, G. and White, T.W. (2007) Gap Junctions: Basic Structure and Function. Journal of Investigative Dermatology, 127, 2516-2524.

[6]   Wang, X., Veruki, M.L., Bukoreshtliev, N.V., Hartveit, E. and Gerdes, H.H. (2010) Animal Cells Connected by Nanotubes Can Be Electrically Coupled through Interposed Gap-Junction Channels. Proceedings of the National Academy of Sciences of the United States of America, 107, 17194-17199.

[7]   Revel, J.P. and Karnovsky, M.J. (1967) Hexagonal Array of Subunits in Intercellular Junctions of the Mouse Heart and Liver. The Journal of Cell Biology, 33, C7-C12.

[8]   Laird, D.W. (2010) The Gap Junction Proteome and Its Relationship to Disease. Trends in Cell Biology, 20, 92-101.

[9]   Bosco, D., Haefliger, J.A. and Meda, P. (2011) Connexins: Key Mediators of Endocrine Function. Physiological Reviews, 91, 1393-1445.

[10]   Laird, D.W. (2006) Life Cycle of Connexins in Health and Disease. Biochemical Journal, 394, 527-543.

[11]   Potolicchio, I., Cigliola, V., Velazquez-Garcia, S., Klee, P., Valjevac, A., Kapic, D., Cosovic, E., Lepara, O., Hadzovic-Dzuvo, A., Mornjacovic, Z. and Meda, P. (2012) Connexin-Dependent Signaling in Neuro-Hormonal Systems. Biochimica et Biophysica Acta, 1818, 1919-1936.

[12]   Pfenniger, A., Chanson, M. and Kwak, B.R. (2013) Connexins in Atherosclerosis. Biochimica et Biophysica Acta, 1828, 157-166.

[13]   Kwak, B.R., Mulhaupt, F., Veillard, N., Gros, D.B. and Mach, F. (2002) Altered Pattern of Vascular Connexin Expression in Atherosclerotic Plaques. Arteriosclerosis, Thrombosis, and Vascular Biology, 22, 225-230.

[14]   Cigliola, V., Chellakudam, V., Arabieter, W. and Meda, P. (2013) Connexins and β-Cell Functions. Diabetes Research and Clinical Practice, 99, 250-259.

[15]   Wright, J.A., Richards, T. and Becker, D. (2012) Connexins and Diabetes. Cardiology Research and Practice, 2012, 496904.

[16]   Tribulova, N., Knezl, V., Okruhlicova, L. and Slezak, J. (2008) Myocardial Gap Junctions: Targets for Novel Approaches in the Prevention of Life-Threatening Cardiac Arrhythmias. Physiological Research, 57, S1-S13.

[17]   Carruba, G., Webber, M.M., Quader, S.T., Amoroso, M., Cocciadiferro, L., Saladino, F., Trosko, J.E. and Castagnetta, L.A. (2002) Regulation of Cell-to-Cell Communication in Non-Tumorigenic and Malignant Human Prostate Epithelial Cells. Prostate, 50, 73-82.

[18]   Stein, E.A. (2001) New Statins and New Doses of Older Statins. Current Atherosclerosis Reports, 3, 14-18.

[19]   Pedersen, T.R. (2010) Pleiotropic Effects of Statins: Evidence against Benefits beyond LDL-Cholesterol Lowering. American Journal of Cardiovascular Drugs, 10, 10-17.

[20]   Massy, Z.A. and Guijarro, C. (2001) Statins: Effects beyond Cholesterol Lowering. Nephrology, Dialysis, Transplantation, 16, 1738-1741.

[21]   de Barros, E.P., Garcia-Pinto, A.B., Machado, P.Y., dos Santos Pereira, M.J. and de Carvalho, J.J. (2011) Rosuvastatin Beneficially Alters the Glomerular Structure of Kidneys from Spontaneously Hypertensive Rats (SHRs). Journal of Molecular Histology, 42, 323-331.

[22]   Blackburn, J.P., Peters, N.S., Yeh, H.I., Rothery, S., Green, C.R. and Severs, N.J. (1995) Upregulation of Connexin43 Gap Junctions during Early Stages of Human Coronary Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 15, 1219-1228.

[23]   van Kempen, M.J. and Jongsma, H.J. (1999) Distribution of Connexin37, Connexin40 and Connexin43 in the Aorta and Coronary Artery of Several Mammals. Histochemistry and Cell Biology, 112, 479-486.

[24]   Wong, C.W., Christen, T., Roth, I., Chadjichristos, C.E., Derouette, J.P., Foglia, B.F., Chanson, M., Goodenough, D.A. and Kwak, B.R. (2006) Connexin37 Protects against Atherosclerosis by Regulating Monocyte Adhesion. Nature Medicine, 12, 950-954.

[25]   Wang, L.H., Chen, J.Z., Sun, Y.L., Zhang, F.R., Zhu, J.H., Hu, S.J. and Wang, D.H. (2005) Statins Reduce Connexin40 and Connexin43 Expression in Atherosclerotic Aorta of Rabbits. International Journal of Cardiology, 100, 467-475.

[26]   Chadjichristos, C.E., Scheckenbach, K.E., van Veen, T.A., Richani Sarieddine, M.Z., de Wit, C., Yang, Z., Roth, I., Bacchetta, M., Viswambharan, H., Foglia, B., Dudez, T., van Kempen, M.J., Coenjaerts, F.E., Miquerol, L., Deutsch, U., Jongsma, H.J., Chanson, M. and Kwak, B.R. (2010) Endothelial-Specific Deletion of Connexin40 Promotes Atherosclerosis by Increasing CD73-Dependent Leukocyte Adhesion. Circulation, 121, 123-131.

[27]   Wang, L., Chen, J., Sun, Y., Zhang, F., Zhu, J., Hu, S. and Wang, D.H. (2005) Regulation of Connexin Expression after Balloon Injury: Possible Mechanisms for Antiproliferative Effect of Statins. American Journal of Hypertension, 18, 1146-1153.

[28]   Gabriels, J.E. and Paul, D.L. (1998) Connexin43 Is Highly Localized to Sites of Disturbed Flow in Rat Aortic Endothelium but Connexin37 and Connexin40 Are More Uniformly Distributed. Circulation Research, 83, 636-643.

[29]   Kwak, B.R., Veillard, N., Pelli, G., Mulhaupt, F., James, R.W., Chanson, M. and Mach, F. (2003) Reduced Connexin43 Expression Inhibits Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice. Circulation, 107, 1033-1039.

[30]   Hansson, G.K. (2005) Inflammation, Atherosclerosis, and Coronary Artery Disease. The New England Journal of Medicine, 352, 1685-1695.

[31]   Rennick, R.E., Connat, J.L., Burnstock, G., Rothery, S., Severs, N.J. and Green, C.R. (1993) Expression of Connexin43 Gap Junctions between Cultured Vascular Smooth Muscle Cells Is Dependent upon Phenotype. Cell and Tissue Research, 271, 323-332.

[32]   Lin, Y.C., Chiang, C.H., Chang, L.T., Sun, C.K., Leu, S., Shao, P.L., Hsieh, M.C., Tsai, T.H., Chua, S., Chung, S.Y., Kao, Y.H. and Yip, H.K. (2013) Simvastatin Attenuates the Additive Effects of TNF-α and IL-18 on the Connexin 43 Up-Regulation and Over-Proliferation of Cultured Aortic Smooth Muscle Cells. Cytokine, 62, 341-351.

[33]   Déglise, S., Martin, D., Probst, H., Saucy, F., Hayoz, D., Waeber, G., Nicod, P., Ris, H.B., Corpataux, J.M. and Haefliger, J.A. (2005) Increased Connexin43 Expression in Human Saphenous Veins in Culture Is Associated with Intimal Hyperplasia. Journal of Vascular Surgery, 41, 1043-1052.

[34]   Shen, J., Wang, L.H., Zheng, L.R., Zhu, J.H. and Hu, S.J. (2010) Lovastatin Inhibits Gap Junctional Communication in Cultured Aortic Smooth Muscle Cells. Journal of Cardiovascular Pharmacology and Therapeutics, 15, 296-302.

[35]   Dubuis, C., May, L., Alonso, F., Luca, L., Mylonaki, I., Meda, P., Delie, F., Jordan, O., Déglise, S., Corpataux, J.M., Saucy, F. and Haefliger, J.A. (2013) Atorvastatin-Loaded Hydrogel Affects the Smooth Muscle Cells of Human Veins. The Journal of Pharmacology and Experimental Therapeutics, 347, 574-581.

[36]   Malewicz, B., Kumar, V.V., Johnson, R.G. and Baumann, W.J. (1990) Lipids in Gap Junction Assembly and Function. Lipids, 25, 419-427.

[37]   Sheu, J.J., Tsai, T.H., Chang, L.T., Chiang, C.H., Youssef, A.A., Sun, C.K., Chang, N.K. and Yip, H.K. (2008) Diabetes Mellitus Downregulates Expression of Connexin43 in Rat Aortic Medial Smooth Muscle Cells and Can Be Reversed by Simvastatin and Losartan Therapy. Chang Gung Medical Journal, 31, 136-144.

[38]   Hou, C.J., Tsai, C.H. and Yeh, H.I. (2008) Endothelial Connexins Are Down-Regulated by Atherogenic Factors. Frontiers in Bioscience, 13, 3549-3557.

[39]   Dlugosová, K., Weismann, P., Bernátová, I., Sotníková, R., Slezák, J. and Okruhlicová, L. (2009) Omega-3 Fatty Acids and Atorvastatin Affect Connexin 43 Expression in the Aorta of Hereditary Hypertriglyceridemic Rats. Canadian Journal of Physiology and Pharmacology, 87, 1074-1082.

[40]   Tsai, C.H., Yeh, H.I., Tian, T.Y., Lee, Y.N., Lu, C.S. and Ko, Y.S. (2004) Down-Regulating Effect of Nicotine on Connexin43 Gap Junctions in Human Umbilical Vein Endothelial Cells Is Attenuated by Statins. European Journal of Cell Biology, 82, 589-595.

[41]   Yeh, H.I., Lu, C.S., Wu, Y.J., Chen, C.C., Hong, R.C., Ko, Y.S., Shiao, M.S., Severs, N.J. and Tsai, C.H. (2003) Reduced Expression of Endothelial Connexin37 and Connexin40 in Hyperlipidemic Mice: Recovery of Connexin37 after 7-Day Simvastatin Treatment. Arteriosclerosis, Thrombosis, and Vascular Biology, 23, 1391-1397.

[42]   Hou, C.J., Tsai, C.H., Su, C.H., Wu, Y.J., Chen, S.J., Chiu, J.J., Shiao, M.S. and Yeh, H.I. (2008) Diabetes Reduces Aortic Endothelial Gap Junctions in ApoE-Deficient Mice: Simvastatin Exacerbates the Reduction. The Journal of Histochemistry and Cytochemistry, 56, 745-752.

[43]   Vozzi, C., Dupont, E., Coppen, S.R., Yeh, H.I. and Severs, N.J. (1999) Chamber-Related Differences in Connexin Expression in Human Heart. Journal of Molecular and Cellular Cardiology, 31, 991-1003.

[44]   Coppen, S.R., Kodama, I., Boyett, M.R., Dobrzynski, H., Takagishi, Y., Honjo, H., Yeh, H.I. and Severs, N.J. (1999) Connexin45, a Major Connexin of the Rabbit Sinoatrial Node, Is Co-Expressed with Connexin43 in a Restricted Zone at the Nodal-Crista Terminalis Border. The Journal of Histochemistry and Cytochemistry, 47, 907-918.

[45]   Kim, E. and Fishman, G.I. (2013) Designer Gap Junctions that Prevent Cardiac Arrhythmias. Trends in Cardiovascular Medicine, 23, 33-38.

[46]   Severs, N.J., Coppen, S.R., Dupont, E., Yeh, H.I., Ko, Y.S. and Matsushita, T. (2004) Gap Junction Alterations in Human Cardiac Disease. Cardiovascular Research, 62, 368-377.

[47]   Anderson, K.P. (2003) Lipid-Lowering Therapy for Prevention of Ventricular Tachyarrhythmias. Journal of the American College of Cardiology, 42, 88-92.

[48]   Bacova, B., Radosinska, J., Knezl, V., Kolenova, L., Weismann, P., Navarova, J., Barancik, M., Mitasikova, M. and Tribulova, N. (2010) Omega-3 Fatty Acids and Atorvastatin Suppress Ventricular Fibrillation Inducibility in Hypertriglyceridemic Rat Hearts: Implication of Intracellular Coupling Protein, Connexin-43. Journal of Physiology and Pharmacology, 61, 717-723.

[49]   Liu, J., Zhang, H. and Nie, W. (2011) Effect of Pravastatin on Gap Junctions and Ventricular Arrhythmias in Rats with Myocardial Infarction. Journal of Clinical Cardiology, 27, 688-690.

[50]   Zhang, A., Zhang, H. and Wu, S. (2010) Immunomodulation by Atorvastatin Upregulates Expression of Gap Junction Proteins in Coxsackievirus B3 (CVB3)-Induced Myocarditis. Inflammation Research, 59, 255-262.

[51]   Wu, S.Y. and Fang, H.Y. (2008) Effects of Pravastatin on Myocardial Connexin 43, IFN-Gamma and IL-10 Expressions in a Murine Model of Viral Myocarditis Induced by Coxsackievirus B3. Zhonghua Xin Xue Guan Bing Za Zhi, 36, 72-76.

[52]   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.

[53]   Laird, D.W. (2005) Connexin Phosphorylation as a Regulatory Event Linked to Gap Junction Internalization and Degradation. Biochimica et Biophysica Acta, 1711, 172-182.

[54]   Celes, M.R., Torres-Dueñas, D., Alves-Filho, J.C., Duarte, D.B., Cunha, F.Q. and Rossi, M.A. (2007) Reduction of Gap and Adherens Junction Proteins and Intercalated Disc Structural Remodeling in the Hearts of Mice Submitted to Severe Cecal Ligation and Puncture Sepsis. Critical Care Medicine, 35, 2176-2185.

[55]   Haefliger, J.A., Krattinger, N., Martin, D., Pedrazzini, T., Capponi, A., Döring, B., Plum, A., Charollais, A., Willecke, K. and Meda, P. (2006) Connexin43-Dependent Mechanism Modulates Renin Secretion and Hypertension. The Journal of Clinical Investigation, 116, 405-413.

[56]   Chen, H.J., Yao, L., Chen, T.G., Yu, M., Wang, L.H. and Chen, J.Z. (2007) Atorvastatin Prevents Connexin43 Remodeling in Hypertrophied Left Ventricular Myocardium of Spontaneously Hypertensive Rats. Chinese Medical Journal, 120, 1902-1907.

[57]   Zhang, F.Z., Wang, L., Zhang, C.T., Pu, J. and Chen, B. (2006) Effect of Atorvastatin on Gap Junction Remodeling in Hypertrophied Myocardium. China Journal of Modern Medicine, 16, 1145-1148.

[58]   Zhang, W.Z., Song, Z.H., Chen, Y.Q., Ma, L., Li, D.D. and Hui, L.L. (2011) Effect of Atorvastatin on the Hypertrophy and Cx40 Expression of Atrial Myocytes Induced by Angiotensin II. Journal of Lanzhou University (Medical Sciences), 37, 15-19.

[59]   Hagendorff, A., Schumacher, B., Kirchhoff, S., Lüderitz, B. and Willecke, K. (1999) Conduction Disturbances and Increased Atrial Vulnerability in Connexin40-Deficient Mice Analyzed by Transesophageal Stimulation. Circulation, 99, 1508-1515.

[60]   Wang, Z., Zhang, Y., Gao, M., Wang, J., Wang, Q., Wang, X., Su, L. and Hou, Y. (2011) Statin Therapy for the Prevention of Atrial Fibrillation: A Meta-Analysis of Randomized Controlled Trials. Pharmacotherapy, 31, 1051-1062.

[61]   Osmak, M. (2012) Statins and Cancer: Current and Future Prospects. Cancer Letters, 324, 1-12.

[62]   Singh, S., Singh, P.P., Singh, A.G., Murad, M.H. and Sanchez, W. (2012) Statins Are Associated with a Reduced Risk of Hepatocellular Cancer: A Systematic Review and Meta-Analysis. Gastroenterology, 144, 323-332.

[63]   Bansal, D., Undela, K., D’Cruz, S. and Schifano, F. (2012) Statin Use and Risk of Prostate Cancer: A Meta-Analysis of Observational Studies. PLoS ONE, 7, Article ID: e46691, 1-11.

[64]   Nielsen, S.F., Nordestgaard, B.G. and Bojesen, S.E. (2012) Statin Use and Reduced Cancer-Related Mortality. The New England Journal of Medicine, 367, 1792-1802.

[65]   Demierre, M.F., Higgins, P.D., Gruber, S.B., Hawk, E. and Lippman, S.M. (2005) Statins and Cancer Prevention. Nature Reviews Cancer, 5, 930-942.

[66]   Ruch, R.J., Madhukar, B.V., Trosko, J.E. and Klaunig, J.E. (1993) Reversal of ras-Induced Inhibition of Gap-Junctional Intercellular Communication, Transformation, and Tumorigenesis by Lovastatin. Molecular Carcinogenesis, 7, 50-59.

[67]   Wei, N., Mi, M.T. and Zhou, Y. (2007) Influences of Lovastatin on Membrane Ion Flow and Intracellular Signaling in Breast Cancer Cells. Cellular & Molecular Biology Letters, 12, 1-15.

[68]   Zhou, Y., Mi, M.T., Zhu, J.D. and Zhang, Q.Y. (2003) Effects of Lovastatin on Proliferation and Gap Junctional Intercellular Communication of Human Breast Cancer Cell MCF-7. Ai Zheng, 22, 257-261.

[69]   Touraine, R.L., Vahanian, N., Ramsey, W.J. and Blaese, R.M. (1998) Enhancement of the Herpes Simplex Virus Thymidine Kinase/Ganciclovir Bystander Effect and Its Antitumor Efficacy in Vivo by Pharmacologic Manipulation of Gap Junctions. Human Gene Therapy, 9, 2385-2391.

[70]   Wang, L., Fu, Y., Peng, J., Wu, D., Yu, M., Xu, C., Wang, Q. and Tao, L. (2013) Simvastatin-Induced Up-Regulation of Gap Junctions Composed of Connexin 43 Sensitize Leydig Tumor Cells to Etoposide: An Involvement of PKC Pathway. Toxicology, 312, 149-157.

[71]   Kandouz, M. and Batist, G. (2010) Gap Junctions and Connexins as Therapeutic Targets in Cancer. Expert Opinion on Therapeutic Targets, 14, 681-692.

[72]   Leinonen, P., Aaltonen, V., Koskela, S., Lehenkari, P., Korkiamaki, T. and Peltonen, J. (2007) Impaired Gap Junction Formation and Intercellular Calcium Signaling in Urinary Bladder Cancer Cells Can Be Improved by Go6976. Cell Communication & Adhesion, 14, 125-136.

[73]   Cesen-Cummings, K., Warner, K.A. and Ruch, R.J. (1998) Role of Protein Kinase C in the Deficient Gap Junctional Intercellular Communication of K-ras-Transformed Murine Lung Epithelial Cells. Anticancer Research, 18, 4343-4346.

[74]   Danesh, F.R., Sadeghi, M.M., Amro, N., Philips, C., Zeng, L., Lin, S., Sahai, A. and Kanwar, Y.S. (2002) 3-Hydroxy-3-Methylglutaryl CoA Reductase Inhibitors Prevent High Glucose-Induced Proliferation of Mesangial Cells via Modulation of Rho GTPase/ p21 Signaling Pathway: Implications for Diabetic Nephropathy. Proceedings of the National Academy of Sciences of the United States of America, 99, 8301-8305.

[75]   Gupta, A., Gupta, V., Thapar, S. and Bhansali, A. (2004) Lipid-Lowering Drug Atorvastatin as an Adjunct in the Management of Diabetic Macular Edema. American Journal of Ophthalmology, 137, 675-682.

[76]   Genetos, D.C., Zhou, Z., Li, Z. and Donahue, H.J. (2012) Age-Related Changes in Gap Junctional Intercellular Communication in Osteoblastic Cells. Journal of Orthopaedic Research, 30, 1979-1984.