Hyperglycemia Suppresses ABCA1 Expression in Vascular Smooth Muscle Cells

Abstract

Hyperglycemia is a major risk factor for atherosclerotic disease. The ATP-binding cassette transporter A1 (ABCA1) functions as a pivotal regulator of lipid efflux from cells to apolipoproteins and is thus involved in lowering the risk of atherosclerosis. In this study, we have examined the glucose-mediated regulation of the ABCA1 gene expression in vascular smooth muscle cells. ABCA1 expression was examined by real-time polymerase chain reaction (PCR), Western blot analysis, and reporter gene assay. The results showed that the expression of the ABCA1 mRNA and protein decreased after the cells were treated with 22.4 mM glucose for 48 h. The transcriptional activity of the ABCA1 promoter paralleled the endogenous expression of the ABCA1 gene. Next, we used inhibitors of certain signal transduction pathways to demonstrate that the glucose-induced ABCA1 suppression is sensitive to the p38-mitogen-activated protein kinase (MAPK) inhibitors. The expression of a constitutively active form of p38-MAPK in the cells inhibited the ABCA1 promoter activity, irrespective of the presence of glucose. A dominant-negative mutant of p38-MAPK abrogated the inhibitory effect of glucose on the ABCA1 promoter activity. These results indicate that the glucose-induced suppression of ABCA1 expression is partially mediated by the activation of the p38-MAPK pathway.

Key words

hyperglycemia - ABCA1 - HDL - smooth muscle cells - diabetes

References

• 1 Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham Study.  JAMA. 1979;  241 2035-2038
• 2 Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.  Diabetes Care. 1993;  16 434-444
• 3 Pugliese G, Tilton RG, Williamson JR. Glucose-induced metabolic imbalances in the pathogenesis of diabetic vascular disease.  Diabetes Metab Rev. 1991;  7 35-59
• 4 Tall AR. Plasma high density lipoproteins. Metabolism and relationship to atherogenesis.  J Clin Invest. 1990;  86 379-384
• 5 Tall AR, Wang N. Tangier disease as a test of the reverse cholesterol transport hypothesis.  J Clin Invest. 2000;  106 1205-1207
• 6 Murao K, Yu X, Imachi H, Cao WM, Chen K, Matsumoto K, Nishiuchi T, Wong NC, Ishida T. Hyperglycemia suppresses hepatic scavenger receptor class B type I expression.  Am J Physiol Endocrinol Metab. 2008;  294 E78-E87
• 7 Nagao S, Murao K, Imachi H, Cao WM, Yu X, Li J, Matsumoto K, Nishiuchi T, Ahmed RA, Wong NC, Ueda K, Ishida T. Platelet derived growth factor regulates ABCA1 expression in vascular smooth muscle cells.  FEBS Lett. 2006;  580 4371-4376
• 8 Yu X, Murao K, Imachi H, Cao WM, Li L, Matsumoto K, Nishiuchi T, Ahmed RA, Wong NC, Kosaka H, Unterman TG, Ishida T. Regulation of scavenger receptor class BI gene expression by angiotensin II in vascular endothelial cells.  Hypertension. 2007;  49 1378-1384
• 9 Langmann T, Porsch-Ozcurumez M, Heimerl S, Probst M, Moehle C, Taher M, Borsukova H, Kielar D, Kaminski WE, Dittrich-Wengenroth E, Schmitz G. Identification of sterol-independent regulatory elements in the human ATP-binding cassette transporter A1 promoter: role of Sp1/3, E-box binding factors, and an oncostatin M-responsive element.  J Biol Chem. 2002;  27 14443-14450
• 10 Imachi H, Murao K, Cao W, Tada S, Taminato T, Wong NC, Takahara J, Ishida T. Expression of human scavenger receptor B1 on and in human platelets.  Arterioscler Thromb Vasc Biol. 2003;  23 898-904
• 11 Begum N, Ragolia L. High glucose and insulin inhibit VSMC MKP-1 expression by blocking iNOS via p38 MAPK activation.  Am J Physio. 2000;  l278 C81-C91
• 12 Igarashi M, Wakasaki H, Takahara N, Ishii H, Jiang ZY, Yamauchi T, Kuboki K, Meier M, Rhodes CJ, King GL. Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways.  J Clin Invest. 1999;  103 185-195
• 13 Serfaty-Lacrosniere C, Civeira F, Lanzberg A, Isaia P, Berg J, Janus ED, Smith MP, Pritchard PH, Frohlich J, Lees RS. Homozygous Tangier disease and cardiovascular disease.  Atherosclerosis. 1994;  107 85-98
• 14 Ruderman NB, Williamson JR, Brownlee M. Glucose and diabetic vascular disease.  FASEB J. 1992;  6 2905-2914
• 15 Haffner SM. Risk constellations in patients with the metabolic syndrome: epidemiology, diagnosis, and treatment patterns.  Am J Med. 2006;  119 S3-S9
• 16 Jenkins AJ, Lyons TJ, Zheng D, Otvos JD, Lackland DT, McGee D, Garvey WT, Klein RL. Serum lipoproteins in the diabetes control and complications trial/epidemiology of diabetes intervention and complications cohort: associations with gender and glycemia.  Diabetes Care. 2003;  26 810-818
• 17 Sampson MJ, Davies IR, Braschi S, Ivory K, Hughes DA. Increased expression of a scavenger receptor (CD36) in monocytes from subjects with Type 2 diabetes.  Atherosclerosis. 2003;  167 129-134

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