Bilirubin metabolism and its role in atherosclerosis

Year 2020, Volume: 5 Issue: 2, 79 - 85, 31.08.2020

Necat Yılmaz , Cemile Öz , Esin Eren , Seçkin Özgür Tekeli

https://doi.org/10.25000/acem.699424

Abstract

Hemoglobin is not an guiltless bystander of the pathophysiology in a number of atherosclerotic diseases. Heme, which is released from hemoglobin or other heme proteins, triggers various pathophysiological consequence, including heme stress as well as intracellular stress. Although heme serves key functions and is tightly controlled, high levels of free heme, which may occur in various pathophysiological conditions, are may hazardous via pro-oxidant, pro-inflammatory, and cytotoxic effects.
Heme oxygenases are heat shock protein enzymes that use heme as a substrate and function as an essential antioxidant adaptive response by all human cells. A major function of heme oxygenases is clearance of heme that accumulate in tissues due to erythrocyte turnover. The potentially toxic free heme is converted by heme oxygenases into carbon monoxide, iron, and biliverdin, the latter of which is reduced to bilirubin. In literature the heme degradation pathway has been demonstrated to play a protective role against the development of atherosclerosis. Because growing evidence suggests that oxidative stress is involved in atherosclerosis.
This review documents the roles of bilurubin in atherosclerosis and focuses on the clinical significance as a potential therapeutic target in atherosclerotic diseases, such as coronary artery disease.

Keywords

Bilirubin, Atherosclerosis, Heme oxygenases, Oxidative stress, Cardiovascular diseases

References

• Kang SJ, Leea C, Kruzliakb P. Effects of serum bilirubin on atherosclerotic processes. Annals of Medicine. 2014;46(3):138-47.
• Vítek L. The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front Pharmacol. 2012;3:55.
• Lin Y, Wang S, Yang Z, Gao L, Zhou Z, Yu P, Wu B.Bilirubin alleviates alum-induced peritonitis through inactivation of NLRP3 inflammasome. Biomed Pharmacother. 2019;116:108973.
• Kang SJ, Lee C, Kruzliak P.Effects of serum bilirubin on atherosclerotic processes. Ann Med. 2014; 46(3):138-47.
• Yilmaz N, Cicek HK, Celik A, Davutoglu V. Diagnostic value of bilirubin concentrations compared with novel and traditional biomarkers in atherosclerosis with coronary artery disease. Saudi Med J. 2006;27(8):1262-4.
• Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235(4792):1043–6.
• Wu TW, Fung KP, Yang CC. Unconjugated bilirubin inhibits the oxidation of human low density lipoprotein beter than Trolox. Life Sci. 1994;54(25):477-81.
• Baranano DE, Rao M, Ferris CD, Snyder SH. Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci U S A. 2002;99(25):16093–8.
• Gazzin S, Vitek L, Watchko J, Shapiro SM, Tiribelli C. A novel perspective on the biology of bilirubin in health and disease. Trends Mol Med. 2016;22(9):758-768.
• Kunutsor SK, Kieneker LM, Burgess S, Bakker SJL, Dullaart RPF. Circulating total bilirubin and future risk of hypertension in the general population: the prevention of renal and vascular end-stage disease (prevend) prospective study and a mendelian randomization approach. J Am Heart Assoc. 2017;6(11):e006503.
• Schwertner HA, Jackson WG, Tolan G. Association of low serum concentration of bilirubin with increased risk of coronary artery disease. Clin Chem. 1994;40(1):18-23.
• Vitek L, Jirsa M, Brodanova M, Kalab M, Marecek Z, Danzig V, et al. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis. 2002;160(2):449–56.
• Novotny L, Vitek L. Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies. Exp Biol Med (Maywood). 2003;228(5):568 – 71.
• Huang SS, Huang PH, Leu HB, Wu TC, Lin SJ, Chen JW. Serum bilirubin predicts long-term clinical outcomes in patients with cardiac syndrome X. Heart. 2010;96(15):1227-32.
• Huang FY, Peng Y, Huang BT, Yang Y, Pu XB, Chen SJ, et al. The correlation between serum total bilirubin and outcomes in patients with different subtypes of coronary artery disease. Clin Chim Acta. 2017;465:101-05.
• Tanaka M, Fukui M, Tomiyasu K, Akabame S, Nakano K, Hasegawa G, et al. Low serum bilirubin concentration is associated with coronary artery calcifi cation (CAC). Atherosclerosis. 2009;206(1):287–91.
• Kang SJ, Kim D, Park HE, Chung GE, Choi SH, Choi SY, et al. Elevated serum bilirubin levels are inversely associated with coronary artery atherosclerosis. Atherosclerosis. 2013;230(2):242–8.
• Lapenna D, Ciofani G, Pierdomenico SD, Giamberardino MA, Ucchino S, Davì G. Association of serum bilirubin with oxidant damage of human atherosclerotic plaques and the severity of atherosclerosis. Clin Exp Med. 2018;18(1):119-24.
• Frikha Z, Ferreira JP, Bozec E, McMurray JJV, Pitt B, Dickstein K, et al. Relation of high serum bilirubin to short-term mortality following a myocardial ınfarction complicated by left ventricular systolic dysfunction (from the high-risk myocardial ınfarction database ınitiative). Am J Cardiol. 2018;121(9):1015-20.
• Xu C, Dong M, Deng Y, Zhang L, Deng F, Zhou J, et al. Relation of direct, ındirect, and total bilirubin to adverse long-term outcomes among patients with acute coronary syndrome. Am J Cardiol. 2019;123(8):1244-48.
• Shen H, Zeng C, Wu X, Liu S, Chen X. Prognostic value of total bilirubin in patients with acute myocardial infarction: A meta-analysis. Medicine (Baltimore). 2019;98(3):e13920.
• Yang L, Huan L, Jinbo L, Hongwei Z, Hongyu W. Is serum total bilirubin a predictor of prognosis in arteriosclerotic cardiovascular disease? :A meta-analysis. Medicine (Baltimore). 2019;98(42):e17544.
• Perlsteın TS, Pande RL, Beckman JA, Creager MA. Serum total bilirubin level and prevalent lowerextremity peripheral arterial disease - National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. Arterioscler Thromb Vasc Biol. 2008;28(1):166-172.
• Zhong K, Wang X, Ma X, Ji X, Sang S, Shao S, et al. Association between serum bilirubin and asymptomatic intracranial atherosclerosis: results from a population-based study. Neurol Sci. 2020.
• Lin LY, Kuo HK, Hwang JJ, Lai LP, Chiang FT, Tseng CD, et al. Serum bilirubin is inversely associated with insulin resistance and metabolic syndrome among children and adolescents. Atherosclerosis. 2009;203(2):563–8.
• Cheriyath P, Gorrepati VS, Peters I, Nookala V, Murphy ME, Srouji N, et al. High total bilirubin as a protective factor for diabetes mellitus: an analysis of NHANES data from 1999–2006. J Clin Med Res. 2010;2(5):201–6.
• Fu YY, Kang KJ, Ahn JM, Kim HR, Na KY, Chae DW, et al. Hyperbilirubinemia reduces the streptozotocin-induced pancreatic damage through attenuating the oxidative stress in the Gunn rat. Tohoku J Exp Med. 2010;222(4):265-73.
• Jıraskova A, Jovanovska J, Skrha J, Vıtek L. Association of low bilirubin levels and promoter variations in UGT1A1 gene with diabetes mellitus type 2 (abstract). Hepatol Int. 2011;5:37.
• Yang M, Ni C, Chang B, Jiang Z, Zhu Y, Tang Y, et al. Association between serum total bilirubin levels and the risk of type 2 diabetes mellitus. Diabetes Res Clin Pract. 2019;152:23-28.
• Nano J, Muka T, Cepeda M, Voortman T, Dhana K, Brahımaj A, et al. Association of circulating total bilirubin with the metabolic syndrome and type 2 diabetes: a systematic review and meta-analysis of observational evidence. Diabetes Metab. 2016;42(6):389-97.
• Peppa M, Urıbarrı J, Vlassara H. The role of advanced glycation end products in the development of atherosclerosis. Curr Diab Rep. 2004;4(1):31-36.
• Vıtek L, Kraslova I, Muchova L, Novotny L, Yamaguchı T. Urinary excretion of oxidative metabolites of bilirubin in subjects with Gilbert Syndrome. J Gastroenterol Hepatol. 2007;22(6):841-45.
• Hwang HJ, Lee SW, Kım SH. Relationship between bilirubin and C-reactive protein. Clin Chem Lab Med. 2011;49(11):1823-28.
• Kang SJ, Kim D, Park HE, Chung GE, Choi SH, Choi SY, et al. Elevated serum bilirubin levels are inversely associated with coronary artery atherosclerosis. Atherosclerosis. 2013;230(2):242-8.
• Keskin E, Karabakan M, Bozkurt A, Hirik E, Karabulut İ, Gunay M, et al. Is there any relationship between serum levels of total bilirubin and the severity of erectile dysfunction? Urologia. 2018;85(3):106-10.
• Erdogan D, Gullu H, Yildirim E, Tok D, Kirbas I, Ciftci O, Baycan ST, Muderrisoglu H.Low serum bilirubin levels are independently and inversely related to impaired flow-mediated vasodilation and increased carotid intima-media thickness in both men and women. Atherosclerosis. 2006 Feb;184(2):431-7.
• Gáll T, Balla G, Balla J. Heme, heme oxygenase, and endoplasmic reticulum stress-a new ınsight into the pathophysiology of vascular diseases. Int J Mol Sci. 2019;20(15).
• Nitti M, Furfaro AL, Mann GE. Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment? Front Physiol. 2020 29;11.23. eCollection 2020.
• Kundur AR, Bulmer AC, Singh I.Unconjugated bilirubin inhibits collagen induced platelet activation. Platelets. 2014;25(1):45-50.