Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended-Release Niacin Therapy

Background— High-density lipoprotein (HDL)–raising therapies are currently under intense evaluation, but the effects of HDL may be highly heterogeneous. We therefore compared the endothelial effects of HDL from healthy subjects and from patients with type 2 diabetes mellitus and low HDL (meeting the criteria for metabolic syndrome), who are frequently considered for HDL-raising therapies. Moreover, in diabetic patients, we examined the impact of extended-release (ER) niacin therapy on the endothelial effects of HDL. Methods and Results— HDL was isolated from healthy subjects (n=10) and patients with type 2 diabetes (n=33) by sequential ultracentrifugation. Effects of HDL on endothelial nitric oxide and superoxide production were characterized by electron spin resonance spectroscopy analysis. Effects of HDL on endothelium-dependent vasodilation and early endothelial progenitor cell–mediated endothelial repair were examined. Patients with diabetes were randomized to a 3-month therapy with ER niacin (1500 mg/d) or placebo, and endothelial effects of HDL were characterized. HDL from healthy subjects stimulated endothelial nitric oxide production, reduced endothelial oxidant stress, and improved endothelium-dependent vasodilation and early endothelial progenitor cell–mediated endothelial repair. In contrast, these beneficial endothelial effects of HDL were not observed in HDL from diabetic patients, which suggests markedly impaired endothelial-protective properties of HDL. ER niacin therapy improved the capacity of HDL to stimulate endothelial nitric oxide, to reduce superoxide production, and to promote endothelial progenitor cell–mediated endothelial repair. Further measurements suggested increased lipid oxidation of HDL in diabetic patients, and a reduction after ER niacin therapy. Conclusions— HDL from patients with type 2 diabetes mellitus and metabolic syndrome has substantially impaired endothelial-protective effects compared with HDL from healthy subjects. ER niacin therapy not only increases HDL plasma levels but markedly improves endothelial-protective functions of HDL in these patients, which is potentially more important. Clinical Trial Registration— clinicaltrials.gov. Identifier: NCT00346970.

[1]  R. Havel,et al.  The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. , 1955, The Journal of clinical investigation.

[2]  R. P. Noble Electrophoretic separation of plasma lipoproteins in agarose gel. , 1968, Journal of lipid research.

[3]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[4]  D. Thelle,et al.  THE TROMSØHEART-STUDY HIGH-DENSITY LIPOPROTEIN AND CORONARY HEART-DISEASE: A PROSPECTIVE CASE-CONTROL STUDY , 1977, The Lancet.

[5]  U. Steinbrecher,et al.  Oxidation of human low density lipoprotein results in derivatization of lysine residues of apolipoprotein B by lipid peroxide decomposition products. , 1987, The Journal of biological chemistry.

[6]  H. Esterbauer,et al.  Continuous monitoring of in vitro oxidation of human low density lipoprotein. , 1989, Free radical research communications.

[7]  T. Kita,et al.  High density lipoprotein loses its effect to stimulate efflux of cholesterol from foam cells after oxidative modification. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[8]  M. Reidy,et al.  Mouse model of arterial injury. , 1993, Circulation research.

[9]  S. Schneider,et al.  Stimulation of low-density lipoprotein oxidation by insulin and insulin like growth factor I. , 1994, Atherosclerosis.

[10]  Takayuki Asahara,et al.  Isolation of Putative Progenitor Endothelial Cells for Angiogenesis , 1997, Science.

[11]  P. Carmeliet,et al.  Vascular wound healing and neointima formation induced by perivascular electric injury in mice. , 1997, The American journal of pathology.

[12]  G. Francis,et al.  High density lipoprotein oxidation: in vitro susceptibility and potential in vivo consequences. , 2000, Biochimica et biophysica acta.

[13]  D. Harrison,et al.  Spin trapping of vascular nitric oxide using colloid Fe(II)-diethyldithiocarbamate. , 2000, Biochemical and biophysical research communications.

[14]  A. Goldberg,et al.  Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia. , 2000, The American journal of cardiology.

[15]  E. Bolson,et al.  Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. , 2001, The New England journal of medicine.

[16]  P. Chambon,et al.  Estradiol Accelerates Reendothelialization in Mouse Carotid Artery Through Estrogen Receptor-α but Not Estrogen Receptor-β , 2001 .

[17]  P. Chambon,et al.  Estradiol Accelerates Reendothelialization in Mouse Carotid Artery Through Estrogen Receptor-&agr; but Not Estrogen Receptor-&bgr; , 2001, Circulation.

[18]  E J Topol,et al.  Association between myeloperoxidase levels and risk of coronary artery disease. , 2001, JAMA.

[19]  Richard G. W. Anderson,et al.  High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase , 2001, Nature Medicine.

[20]  F. Ruschitzka,et al.  High-Density Lipoprotein Restores Endothelial Function in Hypercholesterolemic Men , 2002, Circulation.

[21]  Hua Cai,et al.  Role of p47phox in Vascular Oxidative Stress and Hypertension Caused by Angiotensin II , 2002, Hypertension.

[22]  D. Harrison,et al.  Vascular Oxidative Stress and Endothelial Dysfunction in Patients With Chronic Heart Failure: Role of Xanthine-Oxidase and Extracellular Superoxide Dismutase , 2002, Circulation.

[23]  M. Hayden,et al.  Restoration of Endothelial Function by Increasing High‐Density Lipoprotein in Subjects With Isolated Low High‐Density Lipoprotein , 2003, Circulation.

[24]  Shirin Rahmani,et al.  Inflammatory/Antiinflammatory Properties of High-Density Lipoprotein Distinguish Patients From Control Subjects Better Than High-Density Lipoprotein Cholesterol Levels and Are Favorably Affected by Simvastatin Treatment , 2003, Circulation.

[25]  Steven M Holland,et al.  Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. , 2003, The Journal of clinical investigation.

[26]  M. Trottmann,et al.  Stimulation of CD36 and the key effector of reverse cholesterol transport ATP-binding cassette A1 in monocytoid cells by niacin. , 2004, Biochemical pharmacology.

[27]  G. Assmann,et al.  HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. , 2004, The Journal of clinical investigation.

[28]  D. Fliser,et al.  Erythropoietin regulates endothelial progenitor cells. , 2004, Blood.

[29]  H. Drexler,et al.  Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase , 2004, Circulation.

[30]  Jeannie K. Lee,et al.  Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: A Double-Blind, Placebo-Controlled Study of Extended-Release Niacin on Atherosclerosis Progression in Secondary Prevention Patients Treated With Statins , 2004, Circulation.

[31]  Marlene Goormastic,et al.  Serum Myeloperoxidase Levels Independently Predict Endothelial Dysfunction in Humans , 2004, Circulation.

[32]  Michael Kinter,et al.  Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. , 2004, The Journal of clinical investigation.

[33]  R. Blumenthal,et al.  Low HDL Cholesterol Levels , 2005 .

[34]  P. Barter,et al.  Reconstituted High-Density Lipoproteins Inhibit the Acute Pro-Oxidant and Proinflammatory Vascular Changes Induced by a Periarterial Collar in Normocholesterolemic Rabbits , 2005, Circulation.

[35]  W. März,et al.  Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans , 2005, Circulation.

[36]  Paul Zimmet,et al.  The metabolic syndrome—a new worldwide definition , 2005, The Lancet.

[37]  R. Blumenthal,et al.  Clinical practice. Low HDL cholesterol levels. , 2005, The New England journal of medicine.

[38]  P. Gambert,et al.  Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation , 2006, Diabetologia.

[39]  R. Krauss,et al.  Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement , 2005, Current opinion in cardiology.

[40]  P. Barter,et al.  High-Density Lipoproteins Enhance Progenitor-Mediated Endothelium Repair in Mice , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[41]  Fernando Costa,et al.  Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. , 2006, Current opinion in cardiology.

[42]  MasatakaSata,et al.  Reconstituted High-Density Lipoprotein Stimulates Differentiation of Endothelial Progenitor Cells and Enhances Ischemia-Induced Angiogenesis , 2007 .

[43]  P. Galuppo,et al.  Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes , 2007, Diabetes.

[44]  Jean-Claude Tardif,et al.  Effect of torcetrapib on the progression of coronary atherosclerosis. , 2007, The New England journal of medicine.

[45]  M. Caulfield,et al.  Effects of torcetrapib in patients at high risk for coronary events. , 2007, The New England journal of medicine.

[46]  D. Rader Mechanisms of Disease: HDL metabolism as a target for novel therapies , 2007, Nature Clinical Practice Cardiovascular Medicine.

[47]  H. Drexler,et al.  Oxidant Stress Impairs In Vivo Reendothelialization Capacity of Endothelial Progenitor Cells From Patients With Type 2 Diabetes Mellitus: Restoration by the Peroxisome Proliferator-Activated Receptor-&ggr; Agonist Rosiglitazone , 2007, Circulation.

[48]  John A Wagner,et al.  Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies , 2007, The Lancet.

[49]  C. Obinger,et al.  Hypochlorite-modified high-density lipoprotein acts as a sink for myeloperoxidase in vitro. , 2008, Cardiovascular research.

[50]  Subramaniam Pennathur,et al.  Combined Statin and Niacin Therapy Remodels the High-Density Lipoprotein Proteome , 2008, Circulation.

[51]  N. Brot,et al.  Methionine oxidation impairs reverse cholesterol transport by apolipoprotein A-I , 2008, Proceedings of the National Academy of Sciences.

[52]  J. Liao HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. , 2008, Current atherosclerosis reports.

[53]  Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins , 2008 .

[54]  T. Yue,et al.  Rosiglitazone inhibits hypercholesterolaemia-induced myeloperoxidase upregulation--a novel mechanism for the cardioprotective effects of PPAR agonists. , 2008, Cardiovascular research.

[55]  J. Stockman,et al.  Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial , 2009 .

[56]  M. Fasshauer,et al.  Effects of extended-release niacin on lipid profile and adipocyte biology in patients with impaired glucose tolerance. , 2009, Atherosclerosis.

[57]  High-Density Lipoprotein Transport Through Aortic Endothelial Cells Involves Scavenger Receptor BI and ATP-Binding Cassette Transporter G1 , 2009, Circulation research.