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Review article: Biomedical intelligence

Vol. 142 No. 1314 (2012)

Risky communication in atherosclerosis and thrombus formation

  • Merlijn J. P. M. T Meens
  • Anna Pfenniger
  • Brenda R Kwak
Cite this as:
Swiss Med Wkly. 2012;142:w13553


Atherosclerosis, a progressive disease of medium- and large-sized arteries, constitutes the major cause of death in developed countries, and is becoming increasingly prevalent in developing countries as well. The main consequences of atherosclerosis are myocardial infarction, cerebral infarction and aortic aneurysm. This inflammatory disease is characterised by specific intimal lesions where lipids, leukocytes and smooth muscle cells accumulate in the arterial wall over time. Risk factors for atherosclerosis can mainly be divided into two groups: i) risk factors induced by environment and behaviour (e.g., Western diet, smoking and sedentary lifestyle) and ii) genetic risk factors. Multiple epidemiological studies have associated a single nucleotide polymorphism (SNP) in the GJA4 gene, coding for connexin37 (Cx37), with increased risk for atherosclerosis and myocardial infarction. Connexins form gap junctions or hemi-channels that mediate an exchange of factors between i) the cytosol of two adjacent cells or ii) the cytosol and the extracellular environment, respectively. The GJA4 SNP codes for a proline-to-serine substitution at amino acid 319 in the regulatory C-terminus of the Cx37 protein, thereby altering basic and regulatory properties of its gap junction- and hemi-channels. In this review we discuss current evidence for mechanisms that link the GJA4SNP to atherosclerosis or thrombus formation after plaque rupture.


  1. Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, et al. Heart disease and stroke statistics – 2011 update: a report from the American Heart Association. Circulation. 2011;123(4):e18–e209.
  2. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868–74.
  3. Libby P, Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets. Nat Med. 2002;8(11):1257–62.
  4. Libby P, DiCarli M, Weissleder R. The vascular biology of atherosclerosis and imaging targets. J Nucl Med. 2010;51(Suppl 1):33S–37S.
  5. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473(7347):317–25.
  6. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011;12(3):204–12.
  7. Shibata N, Glass CK. Regulation of macrophage function in inflammation and atherosclerosis. J Lipid Res. 2009;50(Suppl):S277–81.
  8. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med. 1999;340(2):115–26.
  9. Libby P, Okamoto Y, Rocha VZ, Folco E. Inflammation in atherosclerosis: transition from theory to practice. Circ J. 2010;74(2):213–20.
  10. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23 Suppl 1):III27–32.
  11. Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011;14(5):575–85.
  12. Collings A, Raitakari OT, Juonala M, Mansikkaniemi K, Kahonen M, Hutri-Kahonen N, et al. The influence of smoking and homocysteine on subclinical atherosclerosis is modified by the connexin37 C1019T polymorphism – The Cardiovascular Risk in Young Finns Study. Clin Chem Lab Med. 2008;46(8):1102–8.
  13. Smith SC, Jr., Milani RV, Arnett DK, Crouse JR, 3rd, McDermott MM, Ridker PM, et al. Atherosclerotic Vascular Disease Conference: Writing Group II: risk factors. Circulation. 2004;109(21):2613–6.
  14. Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med. 2009;6(1):16–26.
  15. Davies PF, Spaan JA, Krams R. Shear stress biology of the endothelium. Ann Biomed Eng. 2005;33(12):1714–8.
  16. Flammer AJ, Luscher TF. Three decades of endothelium research: from the detection of nitric oxide to the everyday implementation of endothelial function measurements in cardiovascular diseases. Swiss Med Wkly. 2010;140:w13122.
  17. Cominacini L, Rigoni A, Pasini AF, Garbin U, Davoli A, Campagnola M, et al. The binding of oxidized low density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide. J Biol Chem. 2001;276(17):13750–5.
  18. Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev. 2004;84(3):767–801.
  19. Sano H, Sudo T, Yokode M, Murayama T, Kataoka H, Takakura N, et al. Functional blockade of platelet-derived growth factor receptor-beta but not of receptor-alpha prevents vascular smooth muscle cell accumulation in fibrous cap lesions in apolipoprotein E-deficient mice. Circulation. 2001;103(24):2955–60.
  20. Newby AC, Zaltsman AB. Fibrous cap formation or destruction – the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation. Cardiovasc Res. 1999;41(2):345–60.
  21. Yla-Herttuala S, Bentzon JF, Daemen M, Falk E, Garcia-Garcia HM, Herrmann J, et al. Stabilisation of atherosclerotic plaques. Position paper of the European Society of Cardiology (ESC) Working Group on atherosclerosis and vascular biology. Thromb Haemost. 2011;106(1):1–19.
  22. Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2007;4(4):214–25.
  23. Stylianou IM, Bauer RC, Reilly MP, Rader DJ. Genetic basis of atherosclerosis: insights from mice and humans. Circ Res. 2012;110(2):337–55.
  24. Saez JC, Berthoud VM, Branes MC, Martinez AD, Beyer EC. Plasma membrane channels formed by connexins: their regulation and functions. Physiol Rev. 2003;83(4):1359–400.
  25. Kumar NM, Gilula NB. Cloning and characterization of human and rat liver cDNAs coding for a gap junction protein. J Cell Biol. 1986;103(3):767–76.
  26. Sohl G, Willecke K. An update on connexin genes and their nomenclature in mouse and man. Cell Commun Adhes. 2003;10(4-6):173–80.
  27. Unger VM, Kumar NM, Gilula NB, Yeager M. Three-dimensional structure of a recombinant gap junction membrane channel. Science. 1999;283(5405):1176–80.
  28. Musil LS, Goodenough DA. Biochemical analysis of connexin43 intracellular transport, phosphorylation, and assembly into gap junctional plaques. J Cell Biol. 1991;115(5):1357–74.
  29. Martin PE, Evans WH. Incorporation of connexins into plasma membranes and gap junctions. Cardiovasc Res. 2004;62(2):378–87.
  30. Laird DW. Life cycle of connexins in health and disease. Biochem J. 2006;394(Pt 3):527–43.
  31. Bosco D, Haefliger JA, Meda P. Connexins: key mediators of endocrine function. Physiol Rev. 2011;91(4):1393–445.
  32. White TW, Paul DL, Goodenough DA, Bruzzone R. Functional analysis of selective interactions among rodent connexins. Mol Biol Cell. 1995;6(4):459–70.
  33. White TW, Bruzzone R, Wolfram S, Paul DL, Goodenough DA. Selective interactions among the multiple connexin proteins expressed in the vertebrate lens: the second extracellular domain is a determinant of compatibility between connexins. J Cell Biol. 1994;125(4):879–92.
  34. Dahl G, Werner R, Levine E, Rabadan-Diehl C. Mutational analysis of gap junction formation. Biophys J. 1992;62(1):172–80; discussion 180–2.
  35. Dahl G, Levine E, Rabadan-Diehl C, Werner R. Cell/cell channel formation involves disulfide exchange. Eur J Biochem. 1991;197(1):141–4.
  36. Revel JP, Karnovsky MJ. Hexagonal array of subunits in intercellular junctions of the mouse heart and liver. J Cell Biol. 1967;33(3):C7–C12.
  37. Kwak BR, Hermans MM, De Jonge HR, Lohmann SM, Jongsma HJ, Chanson M. Differential regulation of distinct types of gap junction channels by similar phosphorylating conditions. Mol Biol Cell. 1995;6(12):1707–19.
  38. Morley GE, Taffet SM, Delmar M. Intramolecular interactions mediate pH regulation of connexin43 channels. Biophys J. 1996;70(3):1294–302.
  39. Moreno AP. Biophysical properties of homomeric and heteromultimeric channels formed by cardiac connexins. Cardiovasc Res. 2004;62(2):276–86.
  40. Lampe PD, Lau AF. The effects of connexin phosphorylation on gap junctional communication. Int J Biochem Cell Biol. 2004;36(7):1171–86.
  41. Kwak BR, van Veen TA, Analbers LJ, Jongsma HJ. TPA increases conductance but decreases permeability in neonatal rat cardiomyocyte gap junction channels. Exp Cell Res. 1995;220(2):456–63.
  42. Herve JC, Bourmeyster N, Sarrouilhe D. Diversity in protein-protein interactions of connexins: emerging roles. Biochim Biophys Acta. 2004;1662(1-2):22–41.
  43. Alonso F, Boittin FX, Beny JL, Haefliger JA. Loss of connexin40 is associated with decreased endothelium-dependent relaxations and eNOS levels in the mouse aorta. Am J Physiol Heart Circ Physiol. 2010;299(5):H1365–73.
  44. Looft-Wilson RC, Billaud M, Johnstone SR, Straub AC, Isakson BE. Interaction between nitric oxide signaling and gap junctions: Effects on vascular function. Biochim Biophys Acta. 2011.
  45. Pfenniger A, Derouette JP, Verma V, Lin X, Foglia B, Coombs W, et al. Gap junction protein Cx37 interacts with endothelial nitric oxide synthase in endothelial cells. Arterioscler Thromb Vasc Biol. 2010;30(4):827–34.
  46. Solan JL, Lampe PD. Connexin phosphorylation as a regulatory event linked to gap junction channel assembly. Biochim Biophys Acta. 2005;1711(2):154–63.
  47. Angelillo-Scherrer A, Fontana P, Burnier L, Roth I, Sugamele R, Brisset A, et al. Connexin 37 limits thrombus propensity by downregulating platelet reactivity. Circulation. 2011;124(8):930–9.
  48. Odermatt B, Wellershaus K, Wallraff A, Seifert G, Degen J, Euwens C, et al. Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS. J Neurosci. 2003;23(11):4549–59.
  49. Wong CW, Christen T, Roth I, Chadjichristos CE, Derouette JP, Foglia BF, et al. Connexin37 protects against atherosclerosis by regulating monocyte adhesion. Nat Med. 2006;12(8):950–4.
  50. Lopez D, Rodriguez-Sinovas A, Agullo E, Garcia A, Sanchez JA, Garcia-Dorado D. Replacement of connexin 43 by connexin 32 in a knock-in mice model attenuates aortic endothelium-derived hyperpolarizing factor-mediated relaxation. Exp Physiol. 2009;94(10):1088–97.
  51. Kruger O, Beny JL, Chabaud F, Traub O, Theis M, Brix K, et al. Altered dye diffusion and upregulation of connexin37 in mouse aortic endothelium deficient in connexin40. J Vasc Res. 2002;39(2):160–72.
  52. Chadjichristos CE, Scheckenbach KE, van Veen TA, Richani Sarieddine MZ, de Wit C, Yang Z, et al. Endothelial-specific deletion of connexin40 promotes atherosclerosis by increasing CD73-dependent leukocyte adhesion. Circulation. 2010;121(1):123–31.
  53. Simon AM, McWhorter AR. Decreased intercellular dye-transfer and downregulation of non-ablated connexins in aortic endothelium deficient in connexin37 or connexin40. J Cell Sci. 2003;116(Pt 11):2223–36.
  54. Kwak BR, Mulhaupt F, Veillard N, Gros DB, Mach F. Altered pattern of vascular connexin expression in atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2002;22(2):225–30.
  55. Wolfle SE, Schmidt VJ, Hoepfl B, Gebert A, Alcolea S, Gros D, et al. Connexin45 cannot replace the function of connexin40 in conducting endothelium-dependent dilations along arterioles. Circ Res. 2007;101(12):1292–9.
  56. Gabriels JE, Paul DL. Connexin43 is highly localized to sites of disturbed flow in rat aortic endothelium but connexin37 and connexin40 are more uniformly distributed. Circ Res. 1998;83(6):636–43.
  57. Pfenniger A, Wohlwend A, Kwak BR. Mutations in connexin genes and disease. Eur J Clin Invest. 2011;41(1):103–16.
  58. Mandelboim O, Berke G, Fridkin M, Feldman M, Eisenstein M, Eisenbach L. CTL induction by a tumour-associated antigen octapeptide derived from a murine lung carcinoma. Nature. 1994;369(6475):67–71.
  59. Saito T, Barbin A, Omori Y, Yamasaki H. Connexin 37 mutations in rat hepatic angiosarcomas induced by vinyl chloride. Cancer Res. 1997;57(3):375–7.
  60. Saito T, Krutovskikh V, Marion MJ, Ishak KG, Bennett WP, Yamasaki H. Human hemangiosarcomas have a common polymorphism but no mutations in the connexin37 gene. Int J Cancer. 2000;86(1):67–70.
  61. Krutovskikh V, Mironov N, Yamasaki H. Human connexin 37 is polymorphic but not mutated in tumours. Carcinogenesis. 1996;17(8):1761–3.
  62. Boerma M, Forsberg L, Van Zeijl L, Morgenstern R, De Faire U, Lemne C, et al. A genetic polymorphism in connexin 37 as a prognostic marker for atherosclerotic plaque development. J Intern Med. 1999;246(2):211–8.
  63. Derouette JP, Desplantez T, Wong CW, Roth I, Kwak BR, Weingart R. Functional differences between human Cx37 polymorphic hemichannels. J Mol Cell Cardiol. 2009;46(4):499–507.
  64. Morel S, Burnier L, Roatti A, Chassot A, Roth I, Sutter E, et al. Unexpected role for the human Cx37 C1019T polymorphism in tumour cell proliferation. Carcinogenesis. 2010;31(11):1922–31.
  65. Han Y, Xi S, Zhang X, Yan C, Yang Y, Kang J. Association of connexin 37 gene polymorphisms with risk of coronary artery disease in northern Han Chinese. Cardiology. 2008;110(4):260–5.
  66. Leu HB, Chung CM, Chuang SY, Bai CH, Chen JR, Chen JW, et al. Genetic variants of connexin37 are associated with carotid intima-medial thickness and future onset of ischemic stroke. Atherosclerosis. 2011;214(1):101–6.
  67. Listi F, Candore G, Balistreri CR, Caruso M, Incalcaterra E, Hoffmann E, et al. Connexin37 1019 gene polymorphism in myocardial infarction patients and centenarians. Atherosclerosis. 2007;191(2):460–1.
  68. Listi F, Candore G, Lio D, Russo M, Colonna-Romano G, Caruso M, et al. Association between C1019T polymorphism of connexin37 and acute myocardial infarction: a study in patients from Sicily. Int J Cardiol. 2005;102(2):269–71.
  69. Pitha J, Hubacek JA, Pithova P. The connexin 37 (1019C>T) gene polymorphism is associated with subclinical atherosclerosis in women with type 1 and 2 diabetes and in women with central obesity. Physiol Res. 2010;59(6):1029–32.
  70. Yamada Y, Ichihara S, Izawa H, Tanaka M, Yokota M. Genetic risk for coronary artery disease in individuals with or without type 2 diabetes. Mol Genet Metab. 2004;81(4):282–90.
  71. Yamada Y, Izawa H, Ichihara S, Takatsu F, Ishihara H, Hirayama H, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med. 2002;347(24):1916–23.
  72. Yeh HI, Chou Y, Liu HF, Chang SC, Tsai CH, Connexin37 gene polymorphism and coronary artery disease in Taiwan. Int J Cardiol. 2001;81(2-3):251–5.
  73. Collings A, Islam MS, Juonala M, Rontu R, Kahonen M, Hutri-Kahonen N, et al. Associations between connexin37 gene polymorphism and markers of subclinical atherosclerosis: the Cardiovascular Risk in Young Finns study. Atherosclerosis. 2007;195(2):379–84.
  74. Horan PG, Allen AR, Patterson CC, Spence MS, McGlinchey PG, McKeown PP. The connexin 37 gene polymorphism and coronary artery disease in Ireland. Heart. 2006;92(3):395–6.
  75. Hubacek JA, Stanek V, Gebauerova M, Pilipcincova A, Poledne R, Aschermann M, et al. Lack of an association between connexin-37, stromelysin-1, plasminogen activator-inhibitor type 1 and lymphotoxin-alpha genes and acute coronary syndrome in Czech Caucasians. Exp Clin Cardiol. 2010;15(3):e52–6.
  76. Juo SH, Liao YC, Lin HF, Chen PL, Lin WY, Lin RT. Lack of association between a functional genetic variant of connexin 37 and ischemic stroke in a Taiwanese population. Thromb Res. 2012.
  77. Lanfear DE, Jones PG, Marsh S, Cresci S, Spertus JA, McLeod HL. Connexin37 (GJA4) genotype predicts survival after an acute coronary syndrome. Am Heart J. 2007;154(3):561–6.
  78. Wong CW, Christen T, Pfenniger A, James RW, Kwak BR. Do allelic variants of the connexin37 1019 gene polymorphism differentially predict for coronary artery disease and myocardial infarction? Atherosclerosis. 2007;191(2):355–61.
  79. Katakami N, Sakamoto K, Kaneto H, Matsuhisa M, Shimizu I, Ishibashi F, et al. Association between the connexin37 polymorphism and peripheral arterial disease in subjects with type 2 diabetes. Diabetes Care. 2009;32(5):e53–4.
  80. Henttinen T, Jalkanen S, Yegutkin GG. Adherent leukocytes prevent adenosine formation and impair endothelial barrier function by Ecto-5'-nucleotidase/CD73-dependent mechanism. J Biol Chem. 2003;278(27):24888–95.
  81. Kunapuli SP, Daniel JL. P2 receptor subtypes in the cardiovascular system. Biochem J. 1998;336(Pt 3):513–23.
  82. Goldberg GS, Lampe PD, Nicholson BJ. Selective transfer of endogenous metabolites through gap junctions composed of different connexins. Nat Cell Biol. 1999;1(7):457–9.
  83. Leybaert L, Braet K, Vandamme W, Cabooter L, Martin PE, Evans WH. Connexin channels, connexin mimetic peptides and ATP release. Cell Commun Adhes. 2003;10(4-6):251–7.
  84. Derouette JP, Wong C, Burnier L, Morel S, Sutter E, Galan K, et al. Molecular role of Cx37 in advanced atherosclerosis: a micro-array study. Atherosclerosis. 2009;206(1):69–76.
  85. Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol. 2005;25(10):2054–61.
  86. Sluimer JC, Daemen MJ. Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis. J Pathol. 2009;218(1):7–29.
  87. Kolodgie FD, Narula J, Yuan C, Burke AP, Finn AV, Virmani R. Elimination of neoangiogenesis for plaque stabilization: is there a role for local drug therapy? J Am Coll Cardiol. 2007;49(21):2093–101.
  88. Michel JB, Virmani R, Arbustini E, Pasterkamp G. Intraplaque haemorrhages as the trigger of plaque vulnerability. Eur Heart J. 2011;32(16):1977–85, 1985a, 1985b, 1985c.
  89. Kholova I, Dragneva G, Cermakova P, Laidinen S, Kaskenpaa N, Hazes T, et al. Lymphatic vasculature is increased in heart valves, ischaemic and inflamed hearts and in cholesterol-rich and calcified atherosclerotic lesions. Eur J Clin Invest. 2011;41(5):487–97.
  90. Fang JS, Angelov SN, Simon AM, Burt JM. Cx37 deletion enhances vascular growth and facilitates ischemic limb recovery. Am J Physiol Heart Circ Physiol. 2011;301(5):H1872–81.
  91. Fang JS, Angelov SN, Simon AM, Burt JM. Cx40 is required for, and cx37 limits, postischemic hindlimb perfusion, survival and recovery. J Vasc Res. 2012;49(1):2–12.
  92. Kanady JD, Dellinger MT, Munger SJ, Witte MH, Simon AM. Connexin37 and Connexin43 deficiencies in mice disrupt lymphatic valve development and result in lymphatic disorders including lymphedema and chylothorax. Dev Biol. 2011;354(2):253–66.
  93. Sabine A, Agalarov Y, Maby-El Hajjami H, Jaquet M, Hagerling R, Pollmann C, et al. Mechanotransduction, PROX1, and FOXC2 Cooperate to Control Connexin37 and Calcineurin during Lymphatic-Valve Formation. Dev Cell, 2012.
  94. Hirashiki A, Yamada Y, Murase Y, Suzuki Y, Kataoka H, Morimoto Y, et al. Association of gene polymorphisms with coronary artery disease in low- or high-risk subjects defined by conventional risk factors. J Am Coll Cardiol. 2003;42(8):1429–37.