Plasma Apelin is Lower in Patients with Elevated LDL-Cholesterol

Abstract

Hypercholesterolemia is a major risk factor for atherosclerosis. Dysregulation of adipokines contribute to atherosclerotic diseases. Apelin has recently been shown to be secreted by the adipose tissue in association with hyperinsulinemia and inflammation. We searched plasma apelin levels in patients with elevated low density lipoprotein (LDL)-cholesterol having no additional disorder. Thirty-three patients with hypercholesterolemia and 50 age-, sex-, and body mass index-matched healthy controls were evaluated for their apelin, adiponectin and high sensitivity C-reactive protein (hsCRP) levels, and homeostasis model assessment (HOMA) indexes. Plasma apelin-12 and adiponectin were determined by ELISA and RIA, respectively. Plasma apelin levels were lower in patients with elevated LDL-cholesterol compared to healthy controls (p<0.001). Plasma adiponectin concentration was also lower in the dyslipidemic patients (p<0.001). hsCRP levels were similar in the two groups. Fasting plasma glucose was normal in both groups. HOMA indexes in the dyslipidemic group were higher than the controls (p=0.005). A mild to moderate negative correlation with HOMA and positive correlation with high density lipoprotein cholesterol of apelin was found in the dyslipidemic group. Plasma apelin is decreased in non-obese, non-diabetic and normotensive patients with elevated LDL-cholesterol. Low apelin levels in hypercholesterolemia seem associated with insulin resistance, which needs to be investigated in larger populations as well as in other atherosclerotic conditions.

Apelin - hypercholesterolemia - dyslipidemia - low density lipoprotein (LDL)-cholesterol - adiponectin - insulin resistance - homeostasis model assessment (HOMA) - high sensitivity C-reactive protein (hsCRP)

References

• 1 Bluher M, Fasshauer M, Tonjes A, Kratzsch J, Schon MR, Paschke R. Association of interleukin-6, C-reactive protein, interleukin-10 and adiponectin plasma concentrations with measures of obesity, insulin sensitivity and glucose metabolism.  Exp Clin Endocrinol Diabetes. 2005;  113 534-537
• 2 Boucher J, Masri B, Daviaud D, Gesta S, Guigne C, Mazzucotelli A, Castan-Laurell I, Tack I, Knibiehler B, Carpene C, Audigier Y, Saulnier-Blache JS, Valet P. Apelin, a newly identified adipokine up-regulated by insulin and obesity.  Endocrinology. 2005;  146 1764-1771
• 3 Cheng X, Cheng XS, Pang CC. Venous dilator effect of apelin, an endogenous peptide ligand for the orphan APJ receptor, in conscious rats.  Eur J Pharmacol. 2003;  470 171-175
• 4 Daviaud D, Boucher J, Gesta S, Dray C, Guigne C, Quilliot D, Ayav A, Ziegler O, Carpene C, Saulnier-Blache JS, Valet P, Castan-Laurell I. TNFalpha up-regulates apelin expression in human and mouse adipose tissue.  FASEB J. 2006;  20 1528-1530
• 5 Dogru T, Sonmez A, Tasci I, Bozoglu E, Yilmaz MI, Genc H, Erdem G, Gok M, Bingol N, Kilic S, Ozgurtas T, Bingol S. Plasma visfatin levels in patients with newly diagnosed and untreated type 2 diabetes mellitus and impaired glucose tolerance.  Diabetes Res Clin Pract. 2007;;  76 24-29
• 6 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults . Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).  JAMA. 2001;  285 2486-2497
• 7 Ferroni P, Novo S, Davi V, Novo G, Basili S, Davi G. Circulating transforming growth factor-beta1 levels in asymptomatic carotid plaques.  Stroke. 2005;  36 525-526
• 8 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.  Clin Chem. 1972;  18 499-502
• 9 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease.  N Engl J Med. 2005;  352 1685-1695
• 10 Heinonen MV, Purhonen AK, Miettinen P, Paakkonen M, Pirinen E, Alhava E, Akerman K, Herzig KH. Apelin, orexin-A and leptin plasma levels in morbid obesity and effect of gastric banding.  Regul Pept. 2005;  130 7-13
• 11 Hotamisligil GS. Mechanisms of TNF-alpha-induced insulin resistance.  Exp Clin Endocrinol Diabetes. 1999;  107 119-125
• 12 Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.  Arterioscler Thromb Vasc Biol. 2000;  20 1595-1599
• 13 Kasai A, Shintani N, Oda M, Kakuda M, Hashimoto H, Matsuda T, Hinuma S, Baba A. Apelin is a novel angiogenic factor in retinal endothelial cells.  Biochem Biophys Res Commun. 2004;  325 395-400
• 14 Kleinz MJ, Davenport AP. Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells.  Regul Pept. 2004;  118 119-125
• 15 Kraegen EW, Cooney GJ, Ye JM, Thompson AL, Furler SM. The role of lipids in the pathogenesis of muscle insulin resistance and beta cell failure in type II diabetes and obesity.  Exp Clin Endocrinol Diabetes. 2001;  109 S189-201
• 16 Lebovitz HE. Insulin resistance: definition and consequences.  Exp Clin Endocrinol Diabetes. 2001;  109 S135-148
• 17 Lee DK, Cheng R, Nguyen T, Fan T, Kariyawasam AP, Liu Y, Osmond DH, George SR, O'Dowd BF. Characterization of apelin, the ligand for the APJ receptor.  J Neurochem. 2000;  74 34-41
• 18 Lee DK, Saldivia VR, Nguyen T, Cheng R, George SR, O'Dowd BF. Modification of the terminal residue of apelin-13 antagonizes its hypotensive action.  Endocrinology. 2005;  146 231-236
• 19 Li L, Yang G, Li Q, Tang Y, Yang M, Yang H, Li K. Changes and relations of circulating visfatin, apelin, and resistin levels in normal, impaired glucose tolerance, and type 2 diabetic subjects.  Exp Clin Endocrinol Diabetes. 2006;  114 544-548
• 20 Linnemann B, Voigt W, Nobel W, Janka HU. C-reactive protein is a strong independent predictor of death in type 2 diabetes: association with multiple facets of the metabolic syndrome.  Exp Clin Endocrinol Diabetes. 2006;  114 127-134
• 21 Mangge H, Schauenstein K, Stroedter L, Griesl A, Maerz W, Borkenstein M. Low grade inflammation in juvenile obesity and type 1 diabetes associated with early signs of atherosclerosis.  Exp Clin Endocrinol Diabetes. 2004;  112 378-382
• 22 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
• 23 O'Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, Kennedy JL, Shi X, Petronis A, George SR, Nguyen T. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11.  Gene. 1993;  136 355-360
• 24 Parhofer KG. Beyond LDL-cholesterol: HDL-cholesterol as a target for atherosclerosis prevention.  Exp Clin Endocrinol Diabetes. 2005;  113 414-417
• 25 Patel DA, Srinivasan SR, Xu JH, Chen W, Berenson GS. Adiponectin and its correlates of cardiovascular risk in young adults: the Bogalusa Heart Study.  Metabolism. 2006;  55 1551-1557
• 26 Piatti P, Mario C Di, Monti LD, Fragasso G, Sgura F, Caumo A, Setola E, Lucotti P, Galluccio E, Ronchi C, Origgi A, Zavaroni I, Margonato A, Colombo A. Association of insulin resistance, hyperleptinemia, and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting.  Circulation. 2003;  108 2074-2081
• 27 Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men.  JAMA. 2004;  291 1730-1737
• 28 Prabhakaran D, Anand SS. The metabolic syndrome: an emerging risk state for cardiovascular disease.  Vasc Med. 2004;  9 55-68
• 29 Rabin KR, Kamari Y, Avni I, Grossman E, Sharabi Y. Adiponectin: linking the metabolic syndrome to its cardiovascular consequences.  Expert Rev Cardiovasc Ther. 2005;  3 465-471
• 30 Shin MJ, Lee JH, Jang Y, Park E, Oh J, Chung JH, Chung N. Insulin resistance, adipokines, and oxidative stress in nondiabetic, hypercholesterolemic patients: leptin as an 8-epi-prostaglandin F2alpha determinant.  Metabolism. 2006;  55 918-922
• 31 Sonmez A, Dogru T, Tasci I, Yilmaz MI, Pinar M, Naharci I, Bingol N, Kilic S, Demirtas A, Bingol S, Ozgurtas T, Erikci S. The effect of fluvastatin on plasma adiponectin levels in dyslipidaemia.  Clin Endocrinol (Oxf). 2006;  64 567-572
• 32 Sorhede Winzell M, Magnusson C, Ahren B. The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice.  Regul Pept. 2005;  131 12-17
• 33 Stamler J, Daviglus ML, Garside DB, Dyer AR, Greenland P, Neaton JD. Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity.  JAMA. 2000;  284 311-318
• 34 Szokodi I, Tavi P, Foldes G, Voutilainen-Myllyla S, Ilves M, Tokola H, Pikkarainen S, Piuhola J, Rysa J, Toth M, Ruskoaho H. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility.  Circ Res. 2002;  91 434-440
• 35 Taheri S, Murphy K, Cohen M, Sujkovic E, Kennedy A, Dhillo W, Dakin C, Sajedi A, Ghatei M, Bloom S. The effects of centrally administered apelin-13 on food intake, water intake and pituitary hormone release in rats.  Biochem Biophys Res Commun. 2002;  291 1208-1212
• 36 Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, Kawamata Y, Fukusumi S, Hinuma S, Kitada C, Kurokawa T, Onda H, Fujino M. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor.  Biochem Biophys Res Commun. 1998;  251 471-476
• 37 Tatemoto K, Takayama K, Zou MX, Kumaki I, Zhang W, Kumano K, Fujimiya M. The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism.  Regul Pept. 2001;  99 87-92
• 38 Eynatten M von, Hamann A, Twardella D, Nawroth PP, Brenner H, Rothenbacher D. Relationship of adiponectin with markers of systemic inflammation, atherogenic dyslipidemia, and heart failure in patients with coronary heart disease.  Clin Chem. 2006;  52 853-859
• 39 Wallace AM, MacMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A, Sattar N. Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS).  Circulation. 2001;  104 3052-3056
• 40 Weissberg P. Mechanisms modifying atherosclerotic disease - from lipids to vascular biology.  Atherosclerosis. 1999;  147 S3-10
• 41 Yenicesu M, Yilmaz MI, Caglar K, Sonmez A, Eyileten T, Kir T, Acikel C, Bingol N, Oguz Y, Ikizler TA, Vural A. Adiponectin level is reduced and inversely correlated with the degree of proteinuria in type 2 diabetic patients.  Clin Nephrol. 2005;  64 12-19
• 42 Yilmaz MI, Sonmez A, Kilic S, Celik T, Bingol N, Pinar M, Mumcuoglu T, Ozata M. The association of plasma adiponectin levels with hypertensive retinopathy.  Eur J Endocrinol. 2005;  152 233-240

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