The MAP kinase JNK2 mediates cigarette smoke-induced arterial thrombosis

Summary

Despite public awareness of its deleterious effects, smoking remains a major cause of death. Indeed, it is a risk factor for atherothrombotic complications and in line with this, the introduction of smoking ban in public areas reduced smoking-associated cardiovascular complications. Nonetheless, smoking remains a major concern, and molecular mechanisms by which it causes cardiovascular disease are not known. Peripheral blood monocytes from healthy smokers displayed increased JNK2 and tissue factor (TF) gene expression compared to non-smokers (n=15, p<0.05). Similarly, human aortic endothelial cells exposed to cigarette smoke total particulate matter (CS-TPM) revealed increased TF expression mediated by JNK2 (n=4; p<0.05). Wild-type and JNK2^−/− mice were exposed to cigarette smoke for two weeks after which arterial thrombosis was investigated. Wild-type mice exposed to smoke displayed reduced time to thrombotic arterial occlusion (n=8; p<0.05) and increased tissue factor activity (n=7; p<0.05) as compared to wild-type controls (n=6), while JNK2^−/− mice exposed to smoke maintained an unaltered thrombotic potential (n=8; p=NS) and tissue factor activity (n=8) comparable to that of JNK2^−/− and wild-type controls (n=6; p=NS). Smoking caused an increased production of reactive oxygen species (ROS) in wild-type but not in JNK2^−/− mice (n=7; p<0.05 for wild-type mice and n=5–6; p=NS for JNK2^−/− mice). In conclusion, the MAP kinase JNK2 mediates cigarette smoke-induced TF activation, arterial thrombosis and ROS production. These results underscore a major role of JNK2 in smoke-mediated thrombus formation and may offer an attractive target to prevent smoke-related thrombosis in those subjects which do not manage quitting.

Keywords

Thrombosis - animal model - tissue factor

• References

• 1 Ezzati M, Henley SJ, Thun MJ. et al. Role of smoking in global and regional cardiovascular mortality. Circulation 2005; 112: 489-497.
• 2 Ambrose JA, Barua RS. The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol 2004; 43: 1731-1737.
• 3 He Y, Lam TH, Jiang B. et al. Passive smoking and risk of peripheral arterial disease and ischemic stroke in Chinese women who never smoked. Circulation 2008; 118: 1535-1540.
• 4 Benowitz NL, Fitzgerald GA, Wilson M. et al. Nicotine effects on eicosanoid formation and hemostatic function: comparison of transdermal nicotine and cigarette smoking. J Am Coll Cardiol 1993; 22: 1159-1167.
• 5 Miller GJ, Bauer KA, Cooper JA. et al. Activation of the coagulant pathway in cigarette smokers. Thromb Haemost 1998; 79: 549-553.
• 6 Li M, Yu D, Williams KJ. et al. Tobacco smoke induces the generation of procoagulant microvesicles from human monocytes/macrophages. Arterioscler Thromb Vasc Biol 2010; 30: 1818-1824.
• 7 Camici GG, Steffel J, Akhmedov A. et al. Dimethyl sulfoxide inhibits tissue factor expression, thrombus formation, and vascular smooth muscle cell activation: a potential treatment strategy for drug-eluting stents. Circulation 2006; 114: 1512-1521.
• 8 Schroeter MR, Sawalich M, Humboldt T. et al. Cigarette smoke exposure promotes arterial thrombosis and vessel remodeling after vascular injury in apolipoprotein E-deficient mice. J Vasc Res 2008; 45: 480-492.
• 9 Matetzky S, Tani S, Kangavari S. et al. Smoking increases tissue factor expression in atherosclerotic plaques: implications for plaque thrombogenicity. Circulation 2000; 102: 602-604.
• 10 Stahli BE, Camici GG, Tanner FC. Drug-eluting stent thrombosis. Ther Adv Cardiovasc Dis 2009; 03: 45-52.
• 11 Meyers DG, Neuberger JS, He J. Cardiovascular effect of bans on smoking in public places: a systematic review and meta-analysis. J Am Coll Cardiol 2009; 54: 1249-1255.
• 12 Chaudhury H, Zakkar M, Boyle J. et al. c-Jun N-terminal kinase primes endothelial cells at atheroprone sites for apoptosis. Arterioscler Thromb Vasc Biol 2010; 30: 546-553.
• 13 Camici GG, Steffel J, Amanovic I. et al. Rapamycin promotes arterial thrombosis in vivo: implications for everolimus and zotarolimus eluting stents. Eur Heart J 2009; 31: 236-242.
• 14 Stahli BE, Camici GG, Steffel J. et al. Paclitaxel enhances thrombin-induced endothelial tissue factor expression via c-Jun terminal NH2 kinase activation. Circulation Res 2006; 99: 149-155.
• 15 Ricci R, Sumara G, Sumara I. et al. Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science 2004; 306: 1558-1561.
• 16 Khanna AK, Xu J, Mehra MR. Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model. Lab Invest 2012; 92: 224-235.
• 17 Morrow JD, Frei B, Longmire AW. et al. Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage. N Engl J Med 1995; 332: 1198-1203.
• 18 Perez-Rial S, Del Puerto-Nevado L, Gonzalez-Mangado N. et al. Early detection of susceptibility to acute lung inflammation by molecular imaging in mice exposed to cigarette smoke. Mol Imaging 2011; 10: 398-405.
• 19 Shi Y, Luscher TF, Camici GG. Dual role of endothelial nitric oxide synthase in oxidized LDL-induced, p66Shc-mediated oxidative stress in cultured human endothelial cells. PLoS One 2014; 09: e107787
• 20 Hadi HA, Carr CS, Al Suwaidi J. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag 2005; 01: 183-198.
• 21 Gould NS, Min E, Gauthier S. et al. Aging adversely affects the cigarette smoke-induced glutathione adaptive response in the lung. Am J Respir Crit Care Med 2010; 182: 1114-1122.
• 22 Barbieri SS, Zacchi E, Amadio P. et al. Cytokines present in smokers’ serum interact with smoke components to enhance endothelial dysfunction. Cardiovasc Res 2011; 90: 475-483.
• 23 Talukder MA, Johnson WM, Varadharaj S. et al. Chronic cigarette smoking causes hypertension, increased oxidative stress, impaired NO bioavailability, endothelial dysfunction, and cardiac remodeling in mice. Am J Physiol Heart Circ Physiol 2011; 300: H388-396.
• 24 Miura H, Toyama K, Pratt PF. et al. Cigarette smoking impairs Na+-K+-ATPase activity in the human coronary microcirculation. Am J Physiol Heart Circ Physiol 2011; 300: H109-117.
• 25 Syed FF, Beeching NJ. Lower-limb deep-vein thrombosis in a general hospital: risk factors, outcomes and the contribution of intravenous drug use. QJM 2005; 98: 139-145.
• 26 Lowe GD. Common risk factors for both arterial and venous thrombosis. Br J Haematol 2008; 140: 488-495.
• 27 Severinsen MT, Kristensen SR, Johnsen SP. et al. Smoking and venous thromboembolism: a Danish follow-up study. J Thromb Haemost 2009; 07: 1297-1303.
• 28 Braber S, Henricks PA, Nijkamp FP. et al. Inflammatory changes in the airways of mice caused by cigarette smoke exposure are only partially reversed after smoking cessation. Respir Res 2010; 11: 99.
• 29 Steffel J, Hermann M, Greutert H. et al. Celecoxib decreases endothelial tissue factor expression through inhibition of c-Jun terminal NH2 kinase phosphorylation. Circulation 2005; 111: 1685-1689.
• 30 Rong Y, Zhang M, Zhang L. et al. JNK-ATF-2 inhibits thrombomodulin (TM) expression by recruiting histone deacetylase4 (HDAC4) and forming a transcriptional repression complex in the TM promoter. FEBS Lett 2010; 584: 852-858.
• 31 Hoshino S, Yoshida M, Inoue K. et al. Cigarette smoke extract induces endothelial cell injury via JNK pathway. Biochem Biophys Res Commun 2005; 329: 58-63.
• 32 Osto E, Matter CM, Kouroedov A. et al. c-Jun N-terminal kinase 2 deficiency protects against hypercholesterolemia-induced endothelial dysfunction and oxidative stress. Circulation 2008; 118: 2073-2080.
• 33 Song S, Freedman J, Mody M. et al. Porcine von Willebrand factor and thrombin induce the activation of c-Jun amino-terminal kinase (JNK/SAPK) whereas only thrombin induces activation of extracellular signal-related kinase 2 (ERK2) in human platelets. Br J Haematol 2000; 109: 851-856.
• 34 Kauskot A, Adam F, Mazharian A. et al. Involvement of the mitogen-activated protein kinase c-Jun NH2-terminal kinase 1 in thrombus formation. J Biol Chem 2007; 282: 31990-31999.
• 35 Bugaud F, Nadal-Wollbold F, Levy-Toledano S. et al. Regulation of c-jun-NH2 terminal kinase and extracellular-signal regulated kinase in human platelets. Blood 1999; 94: 3800-3805.
• 36 Shi Y, Cosentino F, Camici GG. et al. Oxidized low-density lipoprotein activates p66Shc via lectin-like oxidized low-density lipoprotein receptor-1, protein kinase C-beta, and c-Jun N-terminal kinase kinase in human endothelial cells. Arterioscler Thromb Vasc Biol 2011; 31: 2090-2097.