Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux.
BACKGROUND
Individuals with diabetes mellitus have an increased risk of cardiovascular disease and exhibit platelet hyperreactivity, increasing their resistance to antithrombotic therapies such as aspirin and clopidogrel. Reconstituted high-density lipoprotein (rHDL) has short-term beneficial effects on atherosclerotic plaques, but whether it can effectively reduce the reactivity of diabetic platelets is not known.


RESULTS
Individuals with type 2 diabetes mellitus were infused with placebo or rHDL (CSL-111; 20 mg . kg(-1) . h(-1)) for 4 hours, resulting in an approximately 1.4-fold increase in plasma HDL cholesterol levels. rHDL infusion was associated with a >50% reduction in the ex vivo platelet aggregation response to multiple agonists, an effect that persisted in washed platelets. In vitro studies in platelets from healthy individuals revealed that the inhibitory effects of rHDL on platelet function were time and dose dependent and resulted in a widespread attenuation of platelet function and a 50% reduction in thrombus formation under flow. These effects could be recapitulated, in part, by the isolated phospholipid component of rHDL, which enhanced efflux of cholesterol from platelets and reduced lipid raft assembly. In contrast, the apolipoprotein AI component of rHDL had minimal effect on platelet function, cholesterol efflux, or lipid raft assembly.


CONCLUSIONS
These findings suggest that rHDL therapy is highly effective at inhibiting the heightened reactivity of diabetic platelets, partly through reducing the cholesterol content of platelet membranes. These properties, combined with the known short-term beneficial effects of rHDL on atherosclerotic lesions, suggest that rHDL infusions may be an effective approach to reduce atherothrombotic complications in diabetic individuals. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00395148.
Calkin
Anna C
AC
Diabetes Complications Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Rd Central, Melbourne, Australia 8008. anna.calkin@bakeridi.edu.au
Drew
Brian G
BG
Ono
Akiko
A
Duffy
Stephen J
SJ
Gordon
Michelle V
MV
Schoenwaelder
Simone M
SM
Sviridov
Dmitri
D
Cooper
Mark E
ME
Kingwell
Bronwyn A
BA
Jackson
Shaun P
SP
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D002772:Cholera Toxin / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008075:Lipoproteins, HDL / Q000627:therapeutic use*; D021962:Membrane Microdomains / Q000187:drug effects; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D011994:Recombinant Proteins / Q000627:therapeutic use; D051122:Scavenger Receptors, Class B / Q000502:physiology; D013927:Thrombosis / Q000517:prevention & control
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008075:Lipoproteins, HDL; D011994:Recombinant Proteins; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D002772:Cholera Toxin; D002784:Cholesterol