Abstract
Hypertension is an important public health concern that affects millions globally, leading to a large number of morbidities and fatalities. The etiology of hypertension is complex and multifactorial, and it involves environmental factors, including heavy metals. Cadmium and mercury are toxic elements commonly found in the environment, contributing to hypertension. We aimed to assess the role of cadmium and mercury-induced endothelial dysfunction in the development of hypertension. A narrative review was carried out through database searches. In this review, we discussed the critical roles of cadmium and mercury in the etiology of hypertension and provided new insights into potential mechanisms of their effect, focusing primarily on endothelial dysfunction. Although the mechanisms by which cadmium and mercury induce hypertension have yet to be completely elucidated, evidence for both implicates impaired nitric oxide signaling in their hypertensive etiology.
Keywords: Cadmium, mercury, heavy metals, nitric oxide, hypertension, endothelial dysfunction.
Graphical Abstract
[http://dx.doi.org/10.1289/ehp.10056] [PMID: 17938732]
[http://dx.doi.org/10.3109/1354750X.2016.1153717] [PMID: 26983064]
[http://dx.doi.org/10.1007/s11356-016-7824-5] [PMID: 27778267]
[http://dx.doi.org/10.1016/j.envres.2020.109618] [PMID: 32447086]
[PMID: 26885840]
[http://dx.doi.org/10.1007/s10653-016-9872-7] [PMID: 27670774]
[http://dx.doi.org/10.1007/s11356-013-2039-5] [PMID: 23943080]
[http://dx.doi.org/10.1016/j.envres.2017.01.040] [PMID: 28189876]
[http://dx.doi.org/10.1016/j.envres.2018.11.009] [PMID: 30466011]
[http://dx.doi.org/10.1007/s12011-016-0699-y] [PMID: 27087554]
[http://dx.doi.org/10.3346/jkms.2018.33.e278] [PMID: 30369859]
[http://dx.doi.org/10.1186/s12940-017-0310-9] [PMID: 28950902]
[http://dx.doi.org/10.1016/j.envint.2019.01.041] [PMID: 30684802]
[http://dx.doi.org/10.1038/jhh.2016.67] [PMID: 27629244]
[http://dx.doi.org/10.1038/hr.2014.121] [PMID: 25077919]
[http://dx.doi.org/10.1016/j.envint.2018.08.029] [PMID: 30243183]
[http://dx.doi.org/10.1016/j.taap.2018.05.032] [PMID: 29842852]
[http://dx.doi.org/10.1016/j.scitotenv.2017.11.343] [PMID: 29216461]
[http://dx.doi.org/10.1016/j.toxlet.2007.11.002] [PMID: 18155860]
[http://dx.doi.org/10.1177/0748233709106822] [PMID: 19648216]
[http://dx.doi.org/10.1007/s10534-010-9379-0] [PMID: 20872046]
[http://dx.doi.org/10.1371/journal.pone.0068418] [PMID: 23874620]
[http://dx.doi.org/10.1016/j.etap.2011.03.002] [PMID: 21787725]
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.08.167] [PMID: 23973752]
[http://dx.doi.org/10.1016/j.toxlet.2016.01.014] [PMID: 26809137]
[http://dx.doi.org/10.3390/ijerph2006030040] [PMID: 17159273]
[http://dx.doi.org/10.1016/j.ceca.2007.05.003] [PMID: 17588656]
[http://dx.doi.org/10.1016/j.lfs.2016.10.012] [PMID: 27744053]
[http://dx.doi.org/10.1177/1091581819899039] [PMID: 31934807]
[http://dx.doi.org/10.1080/15555270903143440] [PMID: 31485199]
[http://dx.doi.org/10.1289/ehp.1003012] [PMID: 21220222]
[http://dx.doi.org/10.1007/s00204-009-0437-8] [PMID: 19468715]
[http://dx.doi.org/10.1038/s41370-020-0206-6] [PMID: 32015433]
[http://dx.doi.org/10.1097/JOM.0000000000000560] [PMID: 26641830]
[http://dx.doi.org/10.1056/NEJMra022471] [PMID: 14585942]
[http://dx.doi.org/10.1289/EHP2863] [PMID: 30073953]
[http://dx.doi.org/10.1016/j.envres.2017.01.013] [PMID: 28110211]
[http://dx.doi.org/10.1007/s00420-013-0891-8] [PMID: 23824410]
[http://dx.doi.org/10.1016/j.envres.2013.02.003] [PMID: 23472608]
[http://dx.doi.org/10.1289/ehp.11608] [PMID: 19337510]
[http://dx.doi.org/10.1016/j.envres.2004.04.007] [PMID: 15533337]
[http://dx.doi.org/10.1056/NEJM199510053331412] [PMID: 7666883]
[http://dx.doi.org/10.1093/eurheartj/ehz859] [PMID: 31820000]
[http://dx.doi.org/10.5935/abc.20180098] [PMID: 30226906]
[http://dx.doi.org/10.1016/j.ihj.2018.02.003] [PMID: 30170654]
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11609] [PMID: 30354757]
[http://dx.doi.org/10.1016/j.scitotenv.2008.08.037] [PMID: 18845316]
[http://dx.doi.org/10.1080/10937404.2018.1432025] [PMID: 29446707]
[http://dx.doi.org/10.1016/j.gene.2015.09.061] [PMID: 26428312]
[http://dx.doi.org/10.1152/ajplegacy.1962.202.3.515] [PMID: 13909317]
[http://dx.doi.org/10.1016/S0378-4274(99)00182-4] [PMID: 10643867]
[http://dx.doi.org/10.1007/s12011-018-1359-1] [PMID: 29707746]
[http://dx.doi.org/10.1007/s10534-010-9329-x] [PMID: 20361350]
[http://dx.doi.org/10.1152/ajpcell.1996.271.5.C1424] [PMID: 8944624]
[http://dx.doi.org/10.1016/S0378-4274(03)00265-0] [PMID: 14580892]
[PMID: 15852763]
[http://dx.doi.org/10.1038/sj.bjp.0701573] [PMID: 9484863]
[http://dx.doi.org/10.1191/0960327105ht536oa] [PMID: 16119249]
[http://dx.doi.org/10.1007/BF02898138] [PMID: 21432310]
[http://dx.doi.org/10.1080/13813455.2020.1726403] [PMID: 32067514]
[http://dx.doi.org/10.1016/j.cellbi.2006.02.002] [PMID: 16616865]
[http://dx.doi.org/10.1016/j.taap.2013.07.016] [PMID: 23916567]
[http://dx.doi.org/10.1002/cbin.10070] [PMID: 23404577]
[http://dx.doi.org/10.1093/toxsci/kfm263] [PMID: 17947343]
[PMID: 22550391]
[http://dx.doi.org/10.1038/s41598-017-13694-5] [PMID: 29093498]
[http://dx.doi.org/10.7754/Clin.Lab.2019.181249] [PMID: 31625365]
[http://dx.doi.org/10.2131/jts.40.605] [PMID: 26354377]
[http://dx.doi.org/10.1182/blood-2005-02-0567] [PMID: 15774613]
[http://dx.doi.org/10.2215/CJN.08490910] [PMID: 21642363]
[http://dx.doi.org/10.1016/S0140-6736(01)07184-7] [PMID: 11784629]
[http://dx.doi.org/10.1007/s11356-020-08116-5] [PMID: 32124290]
[http://dx.doi.org/10.1016/0140-6736(92)90865-Z] [PMID: 1347093]
[http://dx.doi.org/10.2174/1381612826666200415172338] [PMID: 32294029]
[http://dx.doi.org/10.1007/s00210-011-0624-z] [PMID: 21448566]
[http://dx.doi.org/10.1038/hr.2011.180] [PMID: 22072109]
[http://dx.doi.org/10.3390/nu6031194] [PMID: 24662163]
[http://dx.doi.org/10.1620/tjem.239.25] [PMID: 27151191]
[http://dx.doi.org/10.1016/j.bbagen.2013.04.016] [PMID: 23618697]
[http://dx.doi.org/10.1016/j.freeradbiomed.2014.06.016] [PMID: 24973647]
[PMID: 842643]
[http://dx.doi.org/10.1159/000323702] [PMID: 21389675]
[PMID: 7462901]
[http://dx.doi.org/10.1016/S0278-6915(82)80296-2] [PMID: 7201956]
[http://dx.doi.org/10.1038/s41598-019-49807-5] [PMID: 31537853]
[http://dx.doi.org/10.1016/j.etap.2019.103198] [PMID: 31154273]
[http://dx.doi.org/10.1016/0041-008X(74)90049-0] [PMID: 4850842]
[http://dx.doi.org/10.1080/00039896.1971.10665964] [PMID: 5558141]
[http://dx.doi.org/10.1016/S0278-6915(97)00042-2] [PMID: 9301656]
[PMID: 9246924]
[http://dx.doi.org/10.1006/enrs.2001.4319] [PMID: 11908936]
[http://dx.doi.org/10.1289/ehp.7928251] [PMID: 488039]
[PMID: 522184]
[PMID: 1893157]
[http://dx.doi.org/10.1016/j.toxlet.2010.04.007] [PMID: 20399841]
[PMID: 4353877]
[http://dx.doi.org/10.1007/s11356-017-0348-9] [PMID: 28975487]
[PMID: 9315231]
[http://dx.doi.org/10.1093/hmg/ddw236] [PMID: 27466201]
[http://dx.doi.org/10.1016/j.placenta.2017.12.004] [PMID: 29405962]
[http://dx.doi.org/10.1016/0378-4274(81)90066-7] [PMID: 6908749]
[http://dx.doi.org/10.1016/0742-8413(93)90139-C] [PMID: 7904909]
[http://dx.doi.org/10.1016/0041-008X(84)90346-6] [PMID: 6506070]
[PMID: 6986793]
[http://dx.doi.org/10.1016/0024-3205(78)90428-9] [PMID: 625192]
[http://dx.doi.org/10.1159/000139503] [PMID: 9286817]
[http://dx.doi.org/10.1152/ajplegacy.1973.225.2.350] [PMID: 4352898]
[http://dx.doi.org/10.1111/j.1476-5381.1983.tb10013.x] [PMID: 6652354]
[PMID: 7589227]
[http://dx.doi.org/10.1007/s10534-006-9017-z] [PMID: 16802071]
[PMID: 11485051]
[http://dx.doi.org/10.1016/S0378-4274(96)03797-6] [PMID: 8960155]
[http://dx.doi.org/10.1161/01.HYP.6.1.20] [PMID: 6141142]
[http://dx.doi.org/10.1007/s12011-017-1150-8] [PMID: 28905315]
[http://dx.doi.org/10.1186/1476-069X-5-29] [PMID: 17032453]
[http://dx.doi.org/10.1016/j.jpeds.2003.10.058] [PMID: 14760255]
[http://dx.doi.org/10.1007/s00420-005-0064-5] [PMID: 16365750]
[http://dx.doi.org/10.1016/0041-008X(87)90185-2] [PMID: 3590186]
[PMID: 17405690]
[http://dx.doi.org/10.3390/ijerph14010074] [PMID: 28085104]
[http://dx.doi.org/10.1080/10408440600845619] [PMID: 16973445]
[http://dx.doi.org/10.1016/j.tiv.2016.10.010] [PMID: 27989546]
[http://dx.doi.org/10.1152/ajpheart.00430.2008] [PMID: 18599595]
[PMID: 31338744]
[http://dx.doi.org/10.1007/s12011-019-01952-8] [PMID: 31745719]
[http://dx.doi.org/10.1111/bcpt.13113] [PMID: 30125472]
[http://dx.doi.org/10.1016/j.cell.2017.04.001] [PMID: 28431241]
[http://dx.doi.org/10.1016/j.bcp.2011.01.008] [PMID: 21295553]
[http://dx.doi.org/10.1161/01.RES.0000121103.03275.EC] [PMID: 14963002]
[http://dx.doi.org/10.1074/jbc.M109.060178] [PMID: 19748889]
[http://dx.doi.org/10.1074/jbc.275.15.11397] [PMID: 10753955]
[http://dx.doi.org/10.1016/j.ecoenv.2018.06.046] [PMID: 29933135]
[http://dx.doi.org/10.1089/ars.2011.4457] [PMID: 22746319]
[http://dx.doi.org/10.1161/01.HYP.0000118518.20331.e8] [PMID: 14993194]
[http://dx.doi.org/10.1016/j.taap.2019.114710] [PMID: 31415774]
[http://dx.doi.org/10.1016/j.tox.2014.11.009] [PMID: 25478804]
[http://dx.doi.org/10.1016/j.envres.2017.02.022] [PMID: 28222365]
[http://dx.doi.org/10.1002/(SICI)1520-670X(2000)13:2<227::AID-JTRA6>3.0.CO;2-F]
[http://dx.doi.org/10.1016/j.neuro.2016.02.010] [PMID: 26945730]
[http://dx.doi.org/10.1007/s10534-015-9823-2] [PMID: 25633799]
[http://dx.doi.org/10.1080/10937404.2017.1289834] [PMID: 28379072]
[http://dx.doi.org/10.1016/j.envres.2003.08.007] [PMID: 15147922]
[http://dx.doi.org/10.1016/j.taap.2013.01.030] [PMID: 23415682]
[http://dx.doi.org/10.1542/peds.105.3.e34] [PMID: 10699136]
[http://dx.doi.org/10.4070/kcj.2013.43.9.581] [PMID: 24174958]
[PMID: 30349568]
[http://dx.doi.org/10.18553/jmcp.2007.13.s8-b.9] [PMID: 17970613]
[http://dx.doi.org/10.1016/j.biopha.2017.07.091] [PMID: 28772209]
[http://dx.doi.org/10.1590/S0100-879X2011007500098] [PMID: 21845340]
[http://dx.doi.org/10.1371/journal.pone.0049005] [PMID: 23145049]
[http://dx.doi.org/10.1016/j.cbpc.2007.10.003] [PMID: 18093879]
[http://dx.doi.org/10.1016/j.lfs.2016.01.033] [PMID: 26804998]
[http://dx.doi.org/10.1111/1440-1681.12578] [PMID: 27061723]
[http://dx.doi.org/10.1016/0378-4274(96)03637-5] [PMID: 8619260]
[http://dx.doi.org/10.1007/s12013-011-9304-3] [PMID: 22020799]
[http://dx.doi.org/10.1021/acs.est.9b00660] [PMID: 31244059]
[PMID: 20228412]
[http://dx.doi.org/10.1177/0748233711427048] [PMID: 22080037]
[http://dx.doi.org/10.1042/CS20110072] [PMID: 21554244]
[http://dx.doi.org/10.1152/ajplegacy.1975.229.1.8] [PMID: 238407]