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CLINICAL RESEARCH: HIGH-DENSITY LIPOPROTEIN

Reconstituted High-Density Lipoprotein Increases Plasma High-Density Lipoprotein Anti-Inflammatory Properties and Cholesterol Efflux Capacity in Patients With Type 2 Diabetes

Sanjay Patel, MBBS^,, Brian G. Drew, PhD_^*, Shirley Nakhla, MApplSc, Stephen J. Duffy, PhD, MBBS, Andrew J. Murphy, PhD_^*, Phillip J. Barter, PhD, MBBS, Kerry-Anne Rye, PhD, Jaye- Chin-Dusting, PhD_^*, Anh Hoang, BSc(Hons)_^*, Dmitri Sviridov, PhD_^*, David S. Celermajer, PhD, MBBS^, and Bronwyn A. Kingwell, PhD^_*,_*

^_* Baker IDI Heart and Diabetes Institute, Melbourne, Australia
Department of Cardiovascular Medicine, Alfred Hospital, Melbourne, Australia
Heart Research Institute, Sydney, Australia
The Faculty of Medicine, University of Sydney, Sydney, Australia

Manuscript received August 25, 2008; revised manuscript received December 2, 2008, accepted December 8, 2008.

^_* Reprint requests and correspondence: Dr. Bronwyn A. Kingwell, P.O. Box 6492, St. Kilda Road Central, Melbourne, Australia, 8008 (Email: bronwyn.kingwell{at}bakeridi.edu.au).

Objectives: Our aim was to investigate the effects of reconstituted high-density lipoprotein (rHDL) infusions on plasma high-density lipoprotein (HDL) anti-inflammatory properties and ex vivo cholesterol efflux in patients with type 2 diabetes.

Background: The anti-inflammatory effects of HDL contribute to protection from cardiovascular events. Individuals with type 2 diabetes are at elevated risk for cardiovascular disease, and typically have low HDL with reduced anti-inflammatory properties.

Methods: Thirteen fasting male patients (mean age 52 years) with type 2 diabetes mellitus received both rHDL (80 mg/kg of apolipoprotein A-I) and a saline placebo on separate occasions in a randomized cross-over design study. Changes in the ability of isolated HDL to influence the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in human coronary artery endothelial cells was the main outcome measure. Other outcome measures included expression of the key integrin, CD11b on patient monocytes, adhesiveness of patient neutrophils to fibrinogen, and the ability of plasma to promote cholesterol efflux to THP-1 macrophages.

Results: Four and 72 h post-rHDL infusion, the anti-inflammatory properties of isolated HDL increased in parallel to their concentration in plasma (by up to 25%, p < 0.01). Participants' peripheral blood monocyte CD11b expression and neutrophil adhesion to a fibrinogen matrix was also reduced 72 h post-rHDL, compared with that seen in placebo (p = 0.02). rHDL increased the capacity of plasma to receive cholesterol from THP-1 macrophages by 1 h up to 72 h post-infusion (by 40% to 60%, p < 0.05).

Conclusions: rHDL infusions have significant, potentially atheroprotective effects in individuals with diabetes, including suppression of inflammation and enhancement of cholesterol efflux.

Key Words: HDL • anti-inflammatory • ICAM • VCAM • cholesterol efflux • monocytes

Abbreviations and Acronyms   apo = apolipoprotein   HDL = high-density lipoprotein   ICAM = intercellular adhesion molecule   rHDL = reconstituted high-density lipoprotein   s = soluble   VCAM = vascular cell adhesion molecule

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