Reconstituted High-Density Lipoprotein Attenuates Platelet Function in Individuals With Type 2 Diabetes Mellitus by Promoting Cholesterol Efflux

Abstract

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. Methods and Results-Individuals with type 2 diabetes mellitus were infused with placebo or rHDL (CSL-111; 20 mg · kg Ϫ1 · h Ϫ1) for 4 hours, resulting in an Ϸ1.4-fold increase in plasma HDL cholesterol levels. rHDL infusion was associated with a Ͼ50% 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. Conclusion-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. Key Words: cholesterol Ⅲ diabetes mellitus Ⅲ platelets T ype 2 diabetes mellitus is a well-known risk factor for cardiovascular disease and is associated with a 3-to 4-fold increase in the incidence of fatal coronary and cerebral ischemic events. 1,2 It is increasingly appreciated that the elevated cardiovascular risk observed in diabetes mellitus is due not only to an increase in atherosclerotic burden but also to enhanced platelet activity, leading to a prothrombotic tendency. Diabetic platelet "hyperreactivity" is caused by a multitude of factors, including increased expression of surface receptors and adhesion molecules, enhanced production of thrombin and thromboxane A 2 , and dysregulated platelet calcium homeostasis. [3][4][5][6] This increase in platelet reactivity reduces the effectiveness of commonly used antiplatelet agents such as aspirin and clopidogrel. 7 As a consequence, more potent antiplatelet therapeutic strategies are increasingly being used to reduce thrombotic complications in diabetes mellitus; however, these approaches have minimal impact on the atherosclerotic lesions themselves, leading to persistent p...

HDL and Atherothrombotic Vascular Disease

“…Study results established that a 40 % increase in HDL cholesterol levels in patients with type 2 diabetes mellitus was associated with a 50-75 % reduction in platelet aggregation (Calkin et al 2009). A similar decrease in the aggregation of platelets was observed when isolated human platelets were incubated with rHDLs or native HDLs in vitro (Calkin et al 2009;Nofer et al 1998;Badrnya et al 2013). Native HDLs and rHDLs not only modulate platelet aggregation but also prevent platelet degranulation and spreading as well as adhesion of platelets to fibrinogen (Calkin et al 2009;Nofer et al 1998;Badrnya et al 2013).…”

“…First, it has been reported that HDLs can block the activation and aggregation of platelets. In a small clinical trail, 13 patients with type 2 diabetes mellitus were randomized to a single infusion of rHDLs (CSL-111) or placebo (Calkin et al 2009). Study results established that a 40 % increase in HDL cholesterol levels in patients with type 2 diabetes mellitus was associated with a 50-75 % reduction in platelet aggregation (Calkin et al 2009).…”

“…In a small clinical trail, 13 patients with type 2 diabetes mellitus were randomized to a single infusion of rHDLs (CSL-111) or placebo (Calkin et al 2009). Study results established that a 40 % increase in HDL cholesterol levels in patients with type 2 diabetes mellitus was associated with a 50-75 % reduction in platelet aggregation (Calkin et al 2009). A similar decrease in the aggregation of platelets was observed when isolated human platelets were incubated with rHDLs or native HDLs in vitro (Calkin et al 2009;Nofer et al 1998;Badrnya et al 2013).…”

Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

“…It is well known that HDL function is critically determined by the components in HDLs such as apoA‐I (apolipoprotein A‐I) 18, 19, 20. Pathological alteration of HDL metabolism imbalances HDL components and thus abrogates the protective effects of HDLs in cardiovascular events 18, 19, 20.…”

High-Density Lipoproteins in Stroke

“…In healthy volunteers receiving low doses of LPS, injection of rHDLs reduced collagen-induced platelet aggregation and modified the procoagulant state associated with endotoxemia (Pajkrt et al 1997). More recently, reconstituted HDL infusion in patients with type 2 diabetes induced a 50-75 % attenuation of platelet aggregation in response to ADP and collagen (Calkin et al 2009). In vitro, this effect was shown to be dose-dependent and remained after removal of rHDLs.…”