Unraveling the Mystery: How High Density Lipoprotein ‘Good’ Cholesterol Goes ‘Bad’?

Yıl 2024, Cilt: 8 Sayı: 2, 177 - 184, 30.08.2024

Oğuz Arslantürk , Ahmet Aydın , Fatih Gümüş , Kübra Aydın , Dilara Zeybek , Hande Canpınar , Murat Güvener

Öz

Background: In recent years, research has highlighted the importance of Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in the progression of atherosclerosis, particularly its interaction with high-density lipoprotein (HDL). Our study aimed to explore the role of dysfunctional High-Density Lipoprotein (HDL) in binding to Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) among patients with Coronary Artery Disease (CAD) and its implications for the advancement of atherosclerosis.

Methods: We enrolled twenty-one patients who underwent multivessel CABG using internal mammary artery (IMA), radial artery (RA), and saphenous vein (SV) grafts between November 2019 and April 2020. Using CD31 to identify endothelial cells, we evaluated LOX-1 expression in all cultured cells.

Results: Our study comprised 21 patients, including 17 (80.9%) males and 4 (19.04%) females. We observed a significant positive correlation between HDL and LOX-1+ expression in specimens extracted from all types of grafts (SV, r=0.60; RA, r=0.48; IMA, r=0.53). Approximately 28% of the variation in LOX-1+ expression for IMA (F=7.03; p<0.05), 36% for SV (F=10.10; p<0.05), and 24% for RA (F=5.64; p<0.05) was attributed to HDL.

Conclusions: Our findings suggest that in cases with heightened LOX-1 receptor expression, HDL binds to LOX-1, leading to a loss of functionality. Monitoring HDL and LOX-1 levels could enhance the prediction of patient responsiveness to treatment and inform appropriate interventions

Anahtar Kelimeler

Atherosclerosis, coronary artery bypass grafts, cardiovascular disease, lipoprotei

Destekleyen Kurum

Hacettepe University Scientific Research Projects Coordination Unit

Proje Numarası

TTU-2019-18259

Gizemi Çözmek: Yüksek Dansiteli Lipoprotein 'İyi' Kolesterol Nasıl 'Kötü' Oluyor?

Öz

Arka Plan: Son yıllarda, araştırmalar aterosklerozun ilerlemesinde, özellikle yüksek yoğunluklu lipoprotein (HDL) ile etkileşimi açısından Lektin-benzeri oksitlenmiş düşük yoğunluklu lipoprotein reseptör-1'in (LOX-1) önemini vurgulamıştır. Çalışmamız, Koroner Arter Hastalığı (CAD) olan hastalarda disfonksiyonel Yüksek Yoğunluklu Lipoprotein'in (HDL) Lektin-benzeri oksitlenmiş düşük yoğunluklu lipoprotein reseptör-1'e (LOX-1) bağlanma rolünü ve ateroskleroz ilerlemesi üzerindeki etkilerini araştırmayı amaçladı.

Yöntemler: Kasım 2019 ile Nisan 2020 tarihleri arasında iç meme arteri (IMA), radial arter (RA) ve safen ven (SV) greftleri kullanılarak çok damarlı CABG geçiren yirmi bir hasta dahil edildi. Endotel hücrelerini tanımlamak için CD31 kullanılarak, tüm kültürlü hücrelerde LOX-1 ifadesi değerlendirildi.

Bulgular: Çalışmamız, 17'si (%80.9) erkek ve 4'ü (%19.04) kadın olmak üzere 21 hastadan oluşmaktadır. Tüm greft türlerinden alınan örneklerde HDL ve LOX-1+ ifadesi arasında anlamlı bir pozitif korelasyon gözlemledik (SV, r=0.60; RA, r=0.48; IMA, r=0.53). IMA için LOX-1+ ifadesindeki varyasyonun yaklaşık %28'i (F=7.03; p<0.05), SV için %36'sı (F=10.10; p<0.05) ve RA için %24'ü (F=5.64; p<0.05) HDL'ye atfedildi.

Sonuçlar: Bulgularımız, yüksek LOX-1 reseptör ifadesi olan durumlarda HDL'in LOX-1'e bağlanarak işlevselliğini kaybettiğini öne sürmektedir. HDL ve LOX-1 seviyelerinin izlenmesi, hastaların tedaviye yanıt verme tahminini artırabilir ve uygun müdahaleleri belirlemeye yardımcı olabilir.

Anahtar Kelimeler

Ateroskleroz, koroner arter bypas greftleri, kardiyovasküler hastalık, lipoprotein

Proje Numarası

TTU-2019-18259

Kaynakça

• 1. Organization tWH. Cardiovascular diseases (CVDs). 2021 [29/05/2021]; Available from: https://www.who.int/en/newsroom/ fact-sheets/detail/cardiovascular-diseases-(cvds).
• 2. M.D. NR. Coronary Artery Disease. In: Fred F. Ferri M.D. FACP, editor. Ferri’s Clinical Advisor 20202020. p. 392-400.
• 3. Curb J, Abbott R, Rodriguez B, Masaki K, Chen R, Sharp D, Tall A. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly. Journal of Lipid Research. 2004;45(5):948-53.
• 4. Sharrett AR, Ballantyne C, Coady S, Heiss G, Sorlie P, Catellier D, Patsch W. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein (a), apolipoproteins AI and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2001;104(10):1108-13.
• 5. Hirata A, Sugiyama D, Watanabe M, Tamakoshi A, Iso H, Kotani K, Kiyama M, Yamada M, Ishikawa S, Murakami Y. Association of extremely high levels of high-density lipoprotein cholesterol with cardiovascular mortality in a pooled analysis of 9 cohort studies including 43,407 individuals: the EPOCH–JAPAN study. Journal of clinical lipidology. 2018;12(3):674-84. e5.
• 6. Hirata A, Okamura T, Sugiyama D, Kuwabara K, Kadota A, Fujiyoshi A, Miura K, Okuda N, Ohkubo T, Okayama A. NIPPON DATA90 Research Group: The relationship between very high levels of serum high-density lipoprotein cholesterol and cause-specific mortality in a 20-year follow-up study of Japanese general population. J Atheroscler Thromb. 2016;23(7):800.
• 7. Ko DT, Alter DA, Guo H, Koh M, Lau G, Austin PC, Booth GL, Hogg W, Jackevicius CA, Lee DS. High-density lipoprotein cholesterol and cause-specific mortality in individuals without previous cardiovascular conditions: the CANHEART study. Journal of the American College of Cardiology. 2016;68(19):2073-83.
• 8. Lloyd-Jones DM, Hong Y, Labarthe D, Mozaffarian D, Appel LJ, Van Horn L, Greenlund K, Daniels S, Nichol G, Tomaselli GF. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic Impact Goal through 2020 and beyond. Circulation. 2010;121(4):586-613.
• 9. Mitra S, Goyal T, Mehta JL. Oxidized LDL, LOX-1 and Atherosclerosis. Cardiovascular Drugs and Therapy. 2011 2011/10/01;25(5):419-29.
• 10. Jin P, Cong S. LOX-1 and atherosclerotic-related diseases. Clinica Chimica Acta. 2019 2019/04/01/;491:24-9.
• 11. Salari A, Hasandokht T, Mahdavi-Roshan M, Kheirkhah J, Gholipour M, Pouradollah Tootkaoni M. Risk factor control, adherence to medication and follow up visit, five years after coronary artery bypass graft surgery. J Cardiovasc Thorac Res. 2016;8(4):152-7.
• 12. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, Byrne RA, Collet JP, Falk V, Head SJ, Jüni P, Kastrati A, Koller A, Kristensen SD, Niebauer J, Richter DJ, Seferovic PM, Sibbing D, Stefanini GG, Windecker S, Yadav R, Zembala MO. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019 Jan 7;40(2):87-165.
• 13. Ogura S, Kakino A, Sato Y, Fujita Y, Iwamoto S, Otsui K, Yoshimoto R, Sawamura T. Lox-1: the multifunctional receptor underlying cardiovascular dysfunction. Circ J. 2009 Nov;73(11):1993- 9.
• 14. Li L, Roumeliotis N, Sawamura T, Renier G. C-reactive protein enhances LOX-1 expression in human aortic endothelial cells: relevance of LOX-1 to C-reactive protein-induced endothelial dysfunction. Circ Res. 2004 Oct 29;95(9):877-83.
• 15. Mehta JL, Sanada N, Hu CP, Chen J, Dandapat A, Sugawara F, Satoh H, Inoue K, Kawase Y, Jishage K-i. Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet. Circulation research. 2007;100(11):1634-42.
• 16. Hu C, Dandapat A, Sun L, Chen J, Marwali MR, Romeo F, Sawamura T, Mehta JL. LOX-1 deletion decreases collagen accumulation in atherosclerotic plaque in low-density lipoprotein receptor knockout mice fed a high-cholesterol diet. Cardiovascular Research. 2008;79(2):287-93.
• 17. Ehara S, Ueda M, Naruko T, Haze K, Itoh A, Otsuka M, Komatsu R, Matsuo T, Itabe H, Takano T, Tsukamoto Y, Yoshiyama M, Takeuchi K, Yoshikawa J, Becker AE. Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes. Circulation. 2001 Apr 17;103(15):1955-60.
• 18. Hofmann A, Brunssen C, Wolk S, Reeps C, Morawietz H. Soluble LOX‐1: A Novel Biomarker in Patients With Coronary Artery Disease, Stroke, and Acute Aortic Dissection? Journal of the American Heart Association. 2020;9(1):e013803.
• 19. Higuma T, Abe N, Tateyama S, Endo T, Shibutani S, Yokoyama H, Hanada K, Yamada M, Tomita H, Hanada H, Osanai T, Kume N, Okumura K. Plasma Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 as a Novel Prognostic Biomarker in Patients With ST-Segment Elevation Acute Myocardial Infarction. Circulation Journal. 2015;79(3):641-8.
• 20. Madsen CM, Varbo A, Tybjærg-Hansen A, Frikke-Schmidt R, Nordestgaard BG. U-shaped relationship of HDL and risk of infectious disease: two prospective population-based cohort studies. Eur Heart J. 2018 Apr 7;39(14):1181-90.
• 21. Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, Hindy G, Hólm H, Ding EL, Johnson T, Schunkert H, Samani NJ, Clarke R, Hopewell JC, Thompson JF, Li M, Thorleifsson G, Newton-Cheh C, Musunuru K, Pirruccello JP, Saleheen D, Chen L, Stewart A, Schillert A, Thorsteinsdottir U, Thorgeirsson G, Anand S, Engert JC, Morgan T, Spertus J, Stoll M, Berger K, Martinelli N, Girelli D, McKeown PP, Patterson CC, Epstein SE, Devaney J, Burnett MS, Mooser V, Ripatti S, Surakka I, Nieminen MS, Sinisalo J, Lokki ML, Perola M, Havulinna A, de Faire U, Gigante B, Ingelsson E, Zeller T, Wild P, de Bakker PI, Klungel OH,Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012 Aug 11;380(9841):572-80.
• 22. Besler C, Heinrich K, Rohrer L, Doerries C, Riwanto M, Shih DM, Chroni A, Yonekawa K, Stein S, Schaefer N, Mueller M, Akhmedov A, Daniil G, Manes C, Templin C, Wyss C, Maier W, Tanner FC, Matter CM, Corti R, Furlong C, Lusis AJ, von Eckardstein A, Fogelman AM, Lüscher TF, Landmesser U. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest. 2011 Jul;121(7):2693-708.
• 23. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJP, Komajda M, Lopez-Sendon J, Mosca L, Tardif J-C, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B. Effects of Torcetrapib in Patients at High Risk for Coronary Events. New England Journal of Medicine. 2007;357(21):2109- 22.
• 24. Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM, Stepanavage M, Liu SX, Gibbons P, Ashraf TB, Zafarino J, Mitchel Y, Barter P. Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease. New England Journal of Medicine. 2010;363(25):2406-15.
• 25. Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. European heart journal. 2017;38(32):2478-86.
• 26. Hirata A, Kakino A, Okamura T, Usami Y, Fujita Y, Kadota A, Fujiyoshi A, Hisamatsu T, Kondo K, Segawa H, Sawamura T, Miura K, Ueshima H. The relationship between serum levels of LOX-1 ligand containing ApoAI as a novel marker of dysfunctional HDL and coronary artery calcification in middle-aged Japanese men. Atherosclerosis. 2020 Nov;313:20-5.