Abstract
Pulmonary hypertension (PH) is a chronic progressive disease characterized by pulmonary vasoconstriction and remodeling. It causes a gradual increase in pulmonary vascular resistance leading to right-sided heart failure, and may be fatal. Chronic exposure to cigarette smoke (CS) is an essential risk factor for PH group 3; however, smoking continues to be prevalent and smoking cessation is reported to be difficult. A majority of smokers exhibit PH, which leads to a concomitant increase in the risk of mortality. The current treatments for PH group 3 focus on vasodilation and long-term oxygen supplementation, and fail to stop or reverse PH-associated continuous vascular remodeling. Recent studies have suggested that pulmonary vascular endothelial dysfunction induced by CS exposure may be an initial event in the natural history of PH, which in turn may be associated with abnormal alterations in connexin (Cx) expression. The relationship between Cx and CS-induced PH development has not yet been directly investigated. Therefore, this review will describe the roles of CS and Cx in the development of PH and discuss the related downstream pathways. We also discuss the possible role of Cx in CS-induced PH. It is hoped that this review may provide new perspectives for early intervention.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alonso F, Krattinger N, Mazzolai L et al (2010) An angiotensin II- and NF-kappaB-dependent mechanism increases connexin 43 in murine arteries targeted by renin-dependent hypertension. Cardiovasc Res 87(1):166–176. https://doi.org/10.1093/cvr/cvq031
Barberà JA, Peinado VI, Santos S, Ramirez J, Roca J, Rodriguez-Roisin R (2001) Reduced expression of endothelial nitric oxide synthase in pulmonary arteries of smokers. Am J Respir Crit Care Med 164(4):709–713. https://doi.org/10.1164/ajrccm.164.4.2101023
Barberà JA, Peinado VI, Santos S (2003) Pulmonary hypertension in chronic obstructive pulmonary disease. Eur Respir J 21(5):892–905. https://doi.org/10.1183/09031936.03.00115402
Benowitz NL (2009) Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annu Rev Pharmacol Toxicol 49:57–71. https://doi.org/10.1146/annurev.pharmtox.48.113006.094742
Beyer EC, Paul DL, Goodenough DA (1987) Connexin43: a protein from rat heart homologous to a gap junction protein from liver. J Cell Biol 105(6 Pt 1):2621–2629. https://doi.org/10.1083/jcb.105.6.2621
Billaud M, Marthan R, Savineau JP, Guibert C (2009) Vascular smooth muscle modulates endothelial control of vasoreactivity via reactive oxygen species production through myoendothelial communications. PLoS ONE 4(7):e6432. https://doi.org/10.1371/journal.pone.0006432
Billaud M, Dahan D, Marthan R, Savineau JP, Guibert C (2011) Role of the gap junctions in the contractile response to agonists in pulmonary artery from two rat models of pulmonary hypertension. Respir Res 12(1):30. https://doi.org/10.1186/1465-9921-12-30
Bouvard C, Genet N, Phan C et al (2020) Connexin-43 is a promising target for pulmonary hypertension due to hypoxaemic lung disease. Eur Respir J 55(3):1900169. https://doi.org/10.1183/13993003.00169-2019
Cao L, Zhang Y, Cao YX, Edvinsson L, Xu CB (2012) Cigarette smoke upregulates rat coronary artery endothelin receptors in vivo. PLoS ONE 7(3):e33008. https://doi.org/10.1371/journal.pone.0033008
Cowan DB, Lye SJ, Langille BL (1998) Regulation of vascular connexin43 gene expression by mechanical loads. Circ Res 82(7):786–793. https://doi.org/10.1161/01.res.82.7.786
Dai J, Zhou Q, Tang H et al (2018) Smooth muscle cell-specific FoxM1 controls hypoxia-induced pulmonary hypertension. Cell Signal 51:119–129. https://doi.org/10.1016/j.cellsig.2018.08.003
Derbyshire ER, Marletta MA (2012) Structure and regulation of soluble guanylate cyclase. Annu Rev Biochem 81:533–559. https://doi.org/10.1146/annurev-biochem-050410-100030
Dhaun N, Webb DJ (2019) Endothelins in cardiovascular biology and therapeutics. Nat Rev Cardiol 16(8):491–502. https://doi.org/10.1038/s41569-019-0176-3
Dhein S, Polontchouk L, Salameh A, Haefliger JA (2002) Pharmacological modulation and differential regulation of the cardiac gap junction proteins connexin 43 and connexin 40. Biol Cell 94(7–8):409–422. https://doi.org/10.1016/s0248-4900(02)00018-7
Donahue HJ, Qu RW, Genetos DC (2017) Joint diseases: from connexins to gap junctions. Nat Rev Rheumatol 14(1):42–51. https://doi.org/10.1038/nrrheum.2017.204
Elton TS, Oparil S, Taylor GR et al (1992) Normobaric hypoxia stimulates endothelin-1 gene expression in the rat. Am J Physiol 263(6 Pt 2):R1260–R1264. https://doi.org/10.1152/ajpregu.1992.263.6.R1260
Farber HW, Gibbs S (2015) Under pressure: pulmonary hypertension associated with left heart disease. Eur Respir Rev : an Off J of the Eur Respir Soc 24(138):665–673. https://doi.org/10.1183/16000617.0059-2015
Freund-Michel V, Muller B, Marthan R, Savineau JP, Guibert C (2016) Expression and role of connexin-based gap junctions in pulmonary inflammatory diseases. Pharmacol Ther 164:105–119. https://doi.org/10.1016/j.pharmthera.2016.04.004
Gairhe S, Bauer NN, Gebb SA, McMurtry IF (2011) Myoendothelial gap junctional signaling induces differentiation of pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 301(4):L527–L535. https://doi.org/10.1152/ajplung.00091.2011
Gairhe S, Bauer NN, Gebb SA, McMurtry IF (2012) Serotonin passes through myoendothelial gap junctions to promote pulmonary arterial smooth muscle cell differentiation. Am J Physiol Lung Cell Mol Physiol 303(9):L767–L777. https://doi.org/10.1152/ajplung.00183.2012
Galiè N, McLaughlin VV, Rubin LJ, Simonneau G (2019) An overview of the 6th World Symposium on Pulmonary Hypertension. Eur Respir J 53(1):1802148. https://doi.org/10.1183/13993003.02148-2018
Gao RJ, Zhang AM, Jia QH et al (2021) The promoting role of Cx43 on the proliferation and migration of arterial smooth muscle cells for angiotensin II-dependent hypertension. Pulm Pharmacol Ther 70:102072. https://doi.org/10.1016/j.pupt.2021.102072
Ghofrani HA, D’Armini AM, Grimminger F et al (2013) Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 369(4):319–329. https://doi.org/10.1056/NEJMoa1209657
Giaid A, Yanagisawa M, Langleben D et al (1993) Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328(24):1732–1739. https://doi.org/10.1056/nejm199306173282402
Gowing LR, Ali RL, Allsop S et al (2015) Global statistics on addictive behaviours: 2014 status report. Addict (abingdon, England) 110(6):904–919. https://doi.org/10.1111/add.12899
Guo C, Ju H, Leung D, Massaeli H, Shi M, Rabinovitch M (2001) A novel vascular smooth muscle chymase is upregulated in hypertensive rats. J Clin Investig 107(6):703–715. https://doi.org/10.1172/jci9997
Haefliger JA, Nicod P, Meda P (2004) Contribution of connexins to the function of the vascular wall. Cardiovasc Res 62(2):345–356. https://doi.org/10.1016/j.cardiores.2003.11.015
Hoeper MM, Humbert M, Souza R et al (2016a) A global view of pulmonary hypertension. Lancet Respir Med 4(4):306–322. https://doi.org/10.1016/s2213-2600(15)00543-3
Hoeper MM, Huscher D, Pittrow D (2016b) Incidence and prevalence of pulmonary arterial hypertension in Germany. Int J Cardiol 203:612–613. https://doi.org/10.1016/j.ijcard.2015.11.001
Hoeper MM, Ghofrani HA, Grünig E, Klose H, Olschewski H, Rosenkranz S (2017) Pulm Hypertens Dtsch Arzteblatt Int 114(5):73–84. https://doi.org/10.3238/arztebl.2017.0073
Hong T, Hill CE (1998) Restricted expression of the gap junctional protein connexin 43 in the arterial system of the rat. J of anat 192(Pt 4 Pt 4):583–593. https://doi.org/10.1046/j.1469-7580.1998.19240583.x
Horinouchi T, Higashi T, Mazaki Y, Miwa S (2016) Carbonyl compounds in the gas phase of cigarette mainstream smoke and their pharmacological properties. Biol Pharm Bull 39(6):909–914. https://doi.org/10.1248/bpb.b16-00025
Hou W, Hu S, Li C et al (2019) Cigarette smoke induced lung barrier dysfunction, EMT, and tissue remodeling: a possible link between COPD and lung cancer. Biomed Res Int 2019:2025636. https://doi.org/10.1155/2019/2025636
Htet M, Nally JE, Shaw A, Foote BE, Martin PE, Dempsie Y (2018) Connexin 43 plays a role in pulmonary vascular reactivity in mice. Int J Mol Sci 19(7):1891. https://doi.org/10.3390/ijms19071891
Humbert M, Galiè N, McLaughlin VV, Rubin LJ, Simonneau G (2019a) An insider view on the world symposium on pulmonary hypertension. Lancet Respir Med 7(6):484–485. https://doi.org/10.1016/s2213-2600(19)30111-0
Humbert M, Guignabert C, Bonnet S et al (2019b) Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J 53(1):1801887. https://doi.org/10.1183/13993003.01887-2018
Isakson BE, Duling BR (2005) Heterocellular contact at the myoendothelial junction influences gap junction organization. Circ Res 97(1):44–51. https://doi.org/10.1161/01.RES.0000173461.36221.2e
Joshi-Mukherjee R, Coombs W, Burrer C, de Mora IA, Delmar M, Taffet SM (2007) Evidence for the presence of a free C-terminal fragment of cx43 in cultured cells. Cell Commun Adhes 14(2–3):75–84. https://doi.org/10.1080/15419060701402320
Kim J, Hwangbo C, Hu X et al (2015) Restoration of impaired endothelial myocyte enhancer factor 2 function rescues pulmonary arterial hypertension. Circulation 131(2):190–199. https://doi.org/10.1161/circulationaha.114.013339
Kishi K, Jin D, Takai S et al (2006) Role of chymase-dependent angiotensin II formation in monocrotaline-induced pulmonary hypertensive rats. Pediatr Res 60(1):77–82. https://doi.org/10.1203/01.pdr.0000219431.45075.d9
Leber L, Beaudet A, Muller A (2021) Epidemiology of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: identification of the most accurate estimates from a systematic literature review. Pulm Circ 11(1):2045894020977300. https://doi.org/10.1177/2045894020977300
Lei Y, Cao YX, Xu CB, Zhang Y (2008) The Raf-1 inhibitor GW5074 and dexamethasone suppress sidestream smoke-induced airway hyperresponsiveness in mice. Respir Res 9(1):71. https://doi.org/10.1186/1465-9921-9-71
Lu Q, Sakhatskyy P, Grinnell K et al (2011) Cigarette smoke causes lung vascular barrier dysfunction via oxidative stress-mediated inhibition of RhoA and focal adhesion kinase. Am J Physiol Lung Cell Mol Physiol 301(6):L847–L857. https://doi.org/10.1152/ajplung.00178.2011
Lu Q, Gottlieb E, Rounds S (2018) Effects of cigarette smoke on pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 314(5):L743–L756. https://doi.org/10.1152/ajplung.00373.2017
Mandras SA, Mehta HS, Vaidya A (2020) Pulmonary Hypertension: A Brief Guide for Clinicians. Mayo Clin Proc 95(9):1978–1988. https://doi.org/10.1016/j.mayocp.2020.04.039
Marasciulo FL, Montagnani M, Potenza MA (2006) Endothelin-1: the yin and yang on vascular function. Curr Med Chem 13(14):1655–1665. https://doi.org/10.2174/092986706777441968
Márquez-Rosado L, Solan JL, Dunn CA, Norris RP, Lampe PD (2012) Connexin43 phosphorylation in brain, cardiac, endothelial and epithelial tissues. Biochem Biophys Acta 8:1985–1992. https://doi.org/10.1016/j.bbamem.2011.07.028
Meşe G, Richard G, White TW (2007) Gap junctions: basic structure and function. J Invest Dermatol 127(11):2516–2524. https://doi.org/10.1038/sj.jid.5700770
Mullin CJ, Klinger JR (2018) Chronic thromboembolic pulmonary hypertension. Heart Fail Clin 14(3):339–351. https://doi.org/10.1016/j.hfc.2018.02.009
Muresan XM, Cervellati F, Sticozzi C et al (2015) The loss of cellular junctions in epithelial lung cells induced by cigarette smoke is attenuated by corilagin. Oxid Med Cell Longev 2015:631758. https://doi.org/10.1155/2015/631758
Ngu NL, McEvoy M (2017) Environmental tobacco smoke and peripheral arterial disease: A review. Atherosclerosis 266:113–120. https://doi.org/10.1016/j.atherosclerosis.2017.09.024
Node K, Kitakaze M, Yoshikawa H, Kosaka H, Hori M (1997) Reversible reduction in plasma concentration of nitric oxide induced by cigarette smoking in young adults. Am J Cardiol 79(11):1538–1541. https://doi.org/10.1016/s0002-9149(97)00189-6
Oakes JM, Xu J, Morris TM et al (2020) Effects of Chronic Nicotine Inhalation on Systemic and Pulmonary Blood Pressure and Right Ventricular Remodeling in Mice. Hypertension (Dallas, Tex: 1979) 75(5):1305–1314. https://doi.org/10.1161/hypertensionaha.119.14608
Okamoto T, Akiyama M, Takeda M, Gabazza EC, Hayashi T, Suzuki K (2009) Connexin32 is expressed in vascular endothelial cells and participates in gap-junction intercellular communication. Biochem Biophys Res Commun 382(2):264–268. https://doi.org/10.1016/j.bbrc.2009.02.148
Ozaki K, Hori T, Ishibashi T, Nishio M, Aizawa Y (2010) Effects of chronic cigarette smoking on endothelial function in young men. J Cardiol 56(3):307–313. https://doi.org/10.1016/j.jjcc.2010.07.003
Peng LQ, Li P, Zhang QL et al (2016) cAMP induction by ouabain promotes endothelin-1 secretion via MAPK/ERK signaling in beating rabbit atria. The Korean J of Physiol & Pharmacol : Off J of the Korean Physiol Soc and the Korean Soc of Pharmacol 20(1):9–14. https://doi.org/10.4196/kjpp.2016.20.1.9
Pfenniger A, Wong C, Sutter E et al (2012) Shear stress modulates the expression of the atheroprotective protein Cx37 in endothelial cells. J Mol Cell Cardiol 53(2):299–309. https://doi.org/10.1016/j.yjmcc.2012.05.011
Pogoda K, Füller M, Pohl U, Kameritsch P (2014) NO, via its target Cx37, modulates calcium signal propagation selectively at myoendothelial gap junctions. Cell Commun Signal 12:33. https://doi.org/10.1186/1478-811x-12-33
Pohl U (2020) Connexins: Key Players in the Control of Vascular Plasticity and Function. Physiol Rev 100(2):525–572. https://doi.org/10.1152/physrev.00010.2019
Prins KW, Thenappan T (2016) World Health Organization Group I Pulmonary Hypertension: Epidemiology and Pathophysiology. Cardiol Clin 34(3):363–374. https://doi.org/10.1016/j.ccl.2016.04.001
Pullamsetti SS, Schermuly RT (2009) Endothelin receptor antagonists in preclinical models of pulmonary hypertension. Eur J Clin Invest 39(Suppl 2):3–13. https://doi.org/10.1111/j.1365-2362.2009.02115.x
Racanelli AC, Kikkers SA, Choi AMK, Cloonan SM (2018) Autophagy and inflammation in chronic respiratory disease. Autophagy 14(2):221–232. https://doi.org/10.1080/15548627.2017.1389823
Ramachandran S, Xie LH, John SA, Subramaniam S, Lal R (2007) A novel role for connexin hemichannel in oxidative stress and smoking-induced cell injury. PLoS ONE 2(8):e712. https://doi.org/10.1371/journal.pone.0000712
Rose L, Prins KW, Archer SL et al (2019) Survival in pulmonary hypertension due to chronic lung disease: Influence of low diffusion capacity of the lungs for carbon monoxide. J Heart Lung Transplant 38(2):145–155. https://doi.org/10.1016/j.healun.2018.09.011
Rounds S, Lu Q (2018) Cigarette smoke alters lung vascular permeability and endothelial barrier function (2017 Grover Conference Series). Pulm Circ 8(3):2045894018794000. https://doi.org/10.1177/2045894018794000
Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA (2003) Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 93(4):280–291. https://doi.org/10.1161/01.Res.0000087541.15600.2b
Saez JC, Berthoud VM, Branes MC, Martinez AD, Beyer EC (2003) Plasma membrane channels formed by connexins: their regulation and functions. Physiol Rev 83(4):1359–1400. https://doi.org/10.1152/physrev.00007.2003
Sahay S (2019) Evaluation and classification of pulmonary arterial hypertension. J Thorac Dis 11(Suppl 14):S1789–S1799. https://doi.org/10.21037/jtd.2019.08.54
Schermuly RT, Stasch JP, Pullamsetti SS et al (2008) Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 32(4):881–891. https://doi.org/10.1183/09031936.00114407
Severs NJ, Rothery S, Dupont E et al (2001) Immunocytochemical analysis of connexin expression in the healthy and diseased cardiovascular system. Microsc Res Tech 52(3):301–322. https://doi.org/10.1002/1097-0029(20010201)52:3%3c301::Aid-jemt1015%3e3.0.Co;2-q
Si R, Zhang Q, Cabrera JTO et al (2020) Chronic hypoxia decreases endothelial connexin 40, attenuates endothelium-dependent hyperpolarization-mediated relaxation in small distal pulmonary arteries, and leads to pulmonary hypertension. J Am Heart Assoc 9(24):e018327. https://doi.org/10.1161/jaha.120.018327
Simonneau G, Montani D, Celermajer DS et al (2019) Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 53(1):1801913. https://doi.org/10.1183/13993003.01913-2018
Smyth JW, Shaw RM (2013) Autoregulation of connexin43 gap junction formation by internally translated isoforms. Cell Rep 5(3):611–618. https://doi.org/10.1016/j.celrep.2013.10.009
Söhl G, Willecke K (2004) Gap junctions and the connexin protein family. Cardiovasc Res 62(2):228–232. https://doi.org/10.1016/j.cardiores.2003.11.013
Soleimani F, Dobaradaran S, De-la-Torre GE, Schmidt TC, Saeedi R (2021) Content of toxic components of cigarette, cigarette smoke vs cigarette butts: A comprehensive systematic review. The Sci of the Total Environ 813:152667. https://doi.org/10.1016/j.scitotenv.2021.152667
Sommer N, Ghofrani HA, Pak O et al (2021) Current and future treatments of pulmonary arterial hypertension. Br J Pharmacol 178(1):6–30. https://doi.org/10.1111/bph.15016
Soon AS, Chua JW, Becker DL (2016) Connexins in endothelial barrier function - novel therapeutic targets countering vascular hyperpermeability. Thromb Haemost 116(5):852–867. https://doi.org/10.1160/th16-03-0210
Straub AC, Johnstone SR, Heberlein KR et al (2010) Site-specific connexin phosphorylation is associated with reduced heterocellular communication between smooth muscle and endothelium. J Vasc Res 47(4):277–286. https://doi.org/10.1159/000265562
Straub AC, Zeigler AC, Isakson BE (2014) The myoendothelial junction: connections that deliver the message. Physiol (bethesda) 29(4):242–249. https://doi.org/10.1152/physiol.00042.2013
Takai S, Jin D, Muramatsu M, Miyazaki M (2004) Chymase as a novel target for the prevention of vascular diseases. Trends Pharmacol Sci 25(10):518–522. https://doi.org/10.1016/j.tips.2004.08.007
Thenappan T, Ormiston ML, Ryan JJ, Archer SL (2018) Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ (clinical Research Ed) 360:j5492. https://doi.org/10.1136/bmj.j5492
Thuringer D, Berthenet K, Cronier L, Solary E, Garrido C (2015) Primary tumor- and metastasis-derived colon cancer cells differently modulate connexin expression and function in human capillary endothelial cells. Oncotarget 6(30):28800–28815. https://doi.org/10.18632/oncotarget.4894
Tsang H, Leiper J, Hou Lao K et al (2013) Role of asymmetric methylarginine and connexin 43 in the regulation of pulmonary endothelial function. Pulm Circ 3(3):675–691. https://doi.org/10.1086/674440
Tsuchiya M, Asada A, Kasahara E, Sato EF, Shindo M, Inoue M (2002) Smoking a single cigarette rapidly reduces combined concentrations of nitrate and nitrite and concentrations of antioxidants in plasma. Circ 105(10):1155–1157. https://doi.org/10.1161/hc1002.105935
Tuder RM, Flook BE, Voelkel NF (1995) Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. The J of clin investig 95(4):1798–1807. https://doi.org/10.1172/jci117858
Tuder RM, Archer SL, Dorfmüller P et al (2013) Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 62(25 Suppl):D4–D12. https://doi.org/10.1016/j.jacc.2013.10.025
Ulrich S, Saxer S, Hasler ED et al (2019) Effect of domiciliary oxygen therapy on exercise capacity and quality of life in patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension: a randomised, placebo-controlled trial. Eur Respir J 54(2):1900276. https://doi.org/10.1183/13993003.002762019
Vachiéry JL, Tedford RJ, Rosenkranz S et al (2019) Pulmonary hypertension due to left heart disease. Eur Respir J 53(1):1801897. https://doi.org/10.1183/13993003.01897-2018
van Rijen HV, van Kempen MJ, Postma S, Jongsma HJ (1998) Tumour necrosis factor alpha alters the expression of connexin43, connexin40, and connexin37 in human umbilical vein endothelial cells. Cytokine 10(4):258–264. https://doi.org/10.1006/cyto.1997.0287
Varela-Carver A, Parker H, Kleinert C, Rimoldi O (2010) Adverse effects of cigarette smoke and induction of oxidative stress in cardiomyocytes and vascular endothelium. Curr Pharm Des 16(23):2551–2558. https://doi.org/10.2174/138161210792062830
Wang HH, Kung CI, Tseng YY et al (2008) Activation of endothelial cells to pathological status by down-regulation of connexin43. Cardiovasc Res 79(3):509–518. https://doi.org/10.1093/cvr/cvn112
Wang T, Han SX, Zhang SF et al (2010) Role of chymase in cigarette smoke-induced pulmonary artery remodeling and pulmonary hypertension in hamsters. Respir Res 11(1):36. https://doi.org/10.1186/1465-9921-11-36
Weissmann N, Hackemack S, Dahal BK et al (2009) The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol 297(4):L658–L665. https://doi.org/10.1152/ajplung.00189.2009
Weissmann N, Lobo B, Pichl A et al (2014) Stimulation of soluble guanylate cyclase prevents cigarette smoke-induced pulmonary hypertension and emphysema. Am J Respir Crit Care Med 189(11):1359–1373. https://doi.org/10.1164/rccm.201311-2037OC
West R (2017) Tobacco smoking: Health impact, prevalence, correlates and interventions. Psychol Health 32(8):1018–1036. https://doi.org/10.1080/08870446.2017.1325890
Xu CB, Lei Y, Chen Q, Pehrson C, Larsson L, Edvinsson L (2010) Cigarette smoke extracts promote vascular smooth muscle cell proliferation and enhances contractile responses in the vasculature and airway. Basic Clin Pharmacol Toxicol 107(6):940–948. https://doi.org/10.1111/j.1742-7843.2010.00610.x
Yeh HI, Rothery S, Dupont E, Coppen SR, Severs NJ (1998) Individual gap junction plaques contain multiple connexins in arterial endothelium. Circ Res 83(12):1248–1263. https://doi.org/10.1161/01.res.83.12.1248
Yu MQ, Liu XS, Wu HX, Xiang M, Xu YJ (2013) ERK1/2 promotes cigarette smoke-induced rat pulmonary artery smooth muscle cells proliferation and pulmonary vascular remodeling via up-regulating cycline1 expression. J of Huazhong Univ of Sci and Technol Med sci = Hua zhong ke ji da xue xue bao Yi xue Ying De wen ban = Huazhong keji daxue xuebao Yixue Yingdewen ban 33(3):315–322. https://doi.org/10.1007/s11596-013-1117-8
Zakynthinos E, Daniil Z, Papanikolaou J, Makris D (2011) Pulmonary hypertension in COPD: pathophysiology and therapeutic targets. Curr Drug Targets 12(4):501–513. https://doi.org/10.2174/138945011794751483
Zhang Y, Xu CB (2020) The roles of endothelin and its receptors in cigarette smoke-associated pulmonary hypertension with chronic lung disease. Pathol Res Pract 216(9):153083. https://doi.org/10.1016/j.prp.2020.153083
Zhang Y, Edvinsson L, Xu CB (2010) Up-regulation of endothelin receptors induced by cigarette smoke–involvement of MAPK in vascular and airway hyper-reactivity. TheScientificWorldJOURNAL 10:2157–2166. https://doi.org/10.1100/tsw.2010.204
Zolty R (2020) Pulmonary arterial hypertension specific therapy: The old and the new. Pharmacol Ther 214:107576. https://doi.org/10.1016/j.pharmthera.2020.107576
Acknowledgements
This study was financially supported by the Youth Program of National Natural Science Foundation of China (81803282), Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi (2020L0193), Open Fund from Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, China (CELLPHYSIOL/SXMU-CPOF202109, CPOF202117) and Shanxi Province Foundation for Returnees (2020-087, 2020-075, 2021-167). This work was also granted by NHC Key Laboratory of Pneumoconiosis in Shanxi (2020-PT320-005).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
None declared.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Qin, X., Gao, A., Hou, X. et al. Connexins may play a critical role in cigarette smoke-induced pulmonary hypertension. Arch Toxicol 96, 1609–1621 (2022). https://doi.org/10.1007/s00204-022-03274-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-022-03274-6