Reduced Population of CD36-/ABCA1+ Macrophages is Correlated with An Increase of Coronary Artery Disease Risk Markers in Type 2 Diabetes Mellitus
Abstract
BACKGROUND: Cluster of differentiation (CD)36 and adenosine triphosphate-binding cassette transporter A1 (ABCA1) are 2 macrophages-expressed receptors that promote cholesterol uptake and efflux, in which their imbalance might be associated with the foam cell formation risk. Type 2 diabetes mellitus (T2DM) has been correlated with the increase of this plaque formation. Therefore, it is necessary to determine whether expression of CD36 and ABCA1 in macrophages are correlated with coronary artery disease (CAD) risk markers in T2DM cases.
METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from 13 diabetic patients and 11 healthy donors. Then, the PBMC-derived macrophages were cultured with supplement of oxidized low-density lipoprotein (ox-LDL) or lipopolysaccharide (LPS). Expression of CD36 and ABCA1 was measured using flowcytometry, meanwhile the supernatant concentration of interleukin (IL)-1b and IL-10 was measured by multiplex immunoassay.
RESULTS: T2DM subjects more likely to have low proportion of CD36-ABCA+ macrophages compared to healthy donors (p=0.041) and it had negative correlation with glucose homeostasis and insulin resistance markers, including fasting blood glucose (FBG, r=-0.408, p=0.048), glycated hemoglobin (HbA1c, r=-0.380, p=0.049), triglyceride glucose index (r=-0,518, p=0.009), and high-sensitivity C-reactive protein (hs-CRP, r=-0.556, p=0.005). Moreover, it also had a negative correlation with atherogenic markers such as triglyceride (r=-0.417, p=0.043), triglyceride/HDL, and LDL/HDL, but had positive correlation with HDL (r=0.540, p=0.007). Most of T2DM subjects had high IL-1β/IL-10 ratio after ox-LDL and LPS stimulation (p=0.02 and p=0.05, respectively).
CONCLUSION: Reduced proportion of CD36-ABCA1+ macrophages followed with high IL-1β/IL-10 can be a marker of CAD in T2DM.
KEYWORDS: type 2 diabetes mellitus, coronary artery disease, macrophages, ABCA1, CD36
References
Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019; 157: 107843, CrossRef.
Kirtaniya AAIK, Lestarini A, Permatananda PANK, Aryastuti AASA. Association of ELMO1 genetic polymorphism (rs741301) with the progression of diabetic kidney disease in Balinese patients with type 2 diabetes mellitus. Mol Cell Biomed Sci. 2023; 7(1): 47-51, CrossRef.
Kartika R, Wibowo H. Impaired function of regulatory T cells in type 2 diabetes mellitus. Mol Cell Biomed Sci. 2020; 4(1): 1-9, CrossRef.
Leon BM, Maddox TM. Diabetes and cardiovascular disease: Epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes. 2015; 6(13): 1246-58, CrossRef.
Beverly JK, Budoff MJ. Atherosclerosis: Pathophysiology of insulin resistance, hyperglycemia, hyperlipidemia, and inflammation. J Diabetes. 2020; 12(2): 102-4, CrossRef.
Francisco CO, Catai AM, Moura-Tonello SC, Arruda LC, Lopes SL, Benze BG, et al. Cytokine profile and lymphocyte subsets in type 2 diabetes. Braz J Med Biol Res. 2016; 49(4): e5062, CrossRef.
Orliaguet L, Dalmas E, Drareni K, Venteclef N, Alzaid F. Mechanisms of macrophage polarization in insulin signaling and sensitivity. Front Endocrinol. 2020; 11: 62, CrossRef.
Tang C, Liu Y, Kessler PS, Vaughan AM, Oram JF. The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor. J Biol Chem. 2009; 284(47): 32336-43, CrossRef.
Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: A dynamic balance. Nat Rev Immunol. 2013; 13(10): 709-21, CrossRef.
Choi HY, Ruel I, Choi S, Genest J. New strategies to promote macrophage cholesterol efflux. Front Cardiovasc Med. 2021; 8: 795868, CrossRef.
Rahaman SO, Lennon DJ, Febbraio M, Podrez EA, Hazen SL, Silverstein RL. A CD36-dependent signaling cascade is necessary for macrophage foam cell formation. Cell Metab. 2006; 4(3): 211-21, CrossRef.
Kennedy DJ, Chen Y, Huang W, Viterna J, Liu J, Westfall K, et al. CD36 and Na/K-ATPase-α1 form a proinflammatory signaling loop in kidney. Hypertension. 2013; 61(1): 216-24, CrossRef.
Liu W, Yin Y, Zhou Z, He M, Dai Y. OxLDL-induced IL-1 beta secretion promoting foam cells formation was mainly via CD36 mediated ROS production leading to NLRP3 inflammasome activation. Inflamm Res. 2014; 63(1): 33-43, CrossRef.
Isoviita PM, Nuotio K, Saksi J, Turunen R, Ijäs P, Pitkäniemi J, et al. An imbalance between CD36 and ABCA1 protein expression favors lipid accumulation in stroke-prone ulcerated carotid plaques. Stroke. 2010; 41(2): 389-93, CrossRef.
Zhu X, Lee JY, Timmins JM, Brown JM, Boudyguina E, Mulya A, et al. Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages. J Biol Chem. 2008; 283(34): 22930-41, CrossRef.
Ma L, Dong F, Zaid M, Kumar A, Zha X. ABCA1 protein enhances Toll-like receptor 4 (TLR4)-stimulated interleukin-10 (IL-10) secretion through protein kinase A (PKA) activation. J Biol Chem. 2012; 287(48): 40502-12, CrossRef.
Meiliana A, Dewi NM, Wijaya A. The high density lipoprotein cholesterol hypothesis revisited. Indones Biomed J. 2018; 10(2): 84-103, CrossRef.
Poznyak AV, Nikiforov NG, Starodubova AV, Popkova TV, Orekhov AN. Macrophages and foam cells: Brief overview of their role, linkage, and targeting potential in atherosclerosis. Biomedicines. 2021; 9(9): 1221, CrossRef.
Jin X, Kruth HS. Culture of macrophage colony-stimulating factor differentiated human monocyte-derived macrophages. J Vis Exp. 2016; (112): 54244, CrossRef.
Poznyak A, Grechko AV, Poggio P, Myasoedova VA, Alfieri V, Orekhov AN. The diabetes mellitus-atherosclerosis connection: The role of lipid and glucose metabolism and chronic inflammation. Int J Mol Sci. 2020; 21(5): 1835, CrossRef.
Liang CP, Han S, Senokuchi T, Tall AR. The macrophage at the crossroads of insulin resistance and atherosclerosis. Circ Res. 2007; 100(11): 1546-55, CrossRef.
Sprenger L, Mader A, Larcher B, Mächler M, Vonbank A, Zanolin-Purin D, et al. Type 2 diabetes and the risk of cardiovascular events in peripheral artery disease versus coronary artery disease. BMJ Open Diabetes Res Care. 2021; 9(2): e002407, CrossRef.
Sargowo D, Handayani O. The association between cardiovascular risk and elevated triglycerides. Indones Biomed J. 2017; 9(1): 17-22, CrossRef.
Aggarwal J, Kathariya MG, Verma PK. LDL-C, NON-HDL-C and APO-B for cardiovascular risk assessment: Looking for the ideal marker. Indian Heart J. 2021; 73(5): 544-8, CrossRef.
Park YM, R Kashyap S, A Major J, Silverstein RL. Insulin promotes macrophage foam cell formation: Potential implications in diabetes-related atherosclerosis. Lab Invest. 2012; 92(8): 1171-80, CrossRef.
Lopez-Carmona MD, Plaza-Seron MC, Vargas-Candela A, Tinahones FJ, Gomez-Huelgas R, Bernal-Lopez MR. CD36 overexpression: A possible etiopathogenic mechanism of atherosclerosis in patients with prediabetes and diabetes. Diabetol Metab Syndr. 2017; 9(1): 55, CrossRef.
Moon JS, Karunakaran U, Suma E, Chung SM, Won KC. The role of CD36 in type 2 diabetes mellitus: β-cell dysfunction and beyond. Diabetes Metab J. 2020; 44(2): 222-33, CrossRef.
Huangfu N, Wang Y, Cheng J, Xu Z, Wang S. Metformin protects against oxidized low density lipoprotein-induced macrophage apoptosis and inhibits lipid uptake. Exp Ther Med. 2018; 15(3): 2485-91, CrossRef.
Patel DC, Albrecht C, Pavitt D, Paul V, Pourreyron C, Newman SP, et al. Type 2 diabetes is associated with reduced ATP-binding cassette transporter A1 gene expression, protein and function. PLoS One. 2011; 6(7): e22142, CrossRef.
Meiliana A, Wijaya A. A closer look at cardioprotective function of HDL: Revise the HDL–cholesterol hypothesis? Indones Biomed J. 2014; 6(1): 17-32, CrossRef.
Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J. The role of interleukin-1 in general pathology. Inflamm Regen. 2019; 39: 12, CrossRef.
Kraakman MJ, Murphy AJ, Jandeleit-Dahm K, Kammoun HL. Macrophage polarization in obesity and type 2 diabetes: Weighing down our understanding of macrophage function? Front Immunol. 2014; 5: 470, CrossRef.
DOI: https://doi.org/10.18585/inabj.v15i6.2625
Copyright (c) 2023 The Prodia Education and Research Institute
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Indexed by:
The Prodia Education and Research Institute