Dysfunctional HDL: From StructureFunction-Relationships to Biomarkers

Reduced plasma levels of HDL-C are associated with an increased risk of CAD and myocardial infarction, as shown in various prospective population studies. However, recent clinical trials on lipid-modifying drugs that increase plasma levels of HDL-C have not shown significant clinical benefit. Notably, in some recent clinical studies, there is no clear association of higher HDL-C levels with a reduced risk of cardiovascular events observed in patients with existing CAD. These observations have prompted researchers to shift from a cholesterol-centric view of HDL towards assessing the function and composition of HDL particles. Of importance, experimental and translational studies have further demonstrated various potential antiatherogenic effects of HDL. HDL has been proposed to promote macrophage reverse cholesterol transport and to protect endothelial cell functions by prevention of oxidation of LDL and its adverse endothelial effects. Furthermore, HDL from healthy subjects can directly stimulate endothelial cell production of nitric oxide and exert anti-inflammatory and antiapoptotic effects. Of note, increasing evidence suggests that the vascular effects of HDL can be highly heterogeneous and HDL may lose important antiatherosclerotic properties and turn dysfunctional in patients with chronic inflammatory disorders. A greater understanding of mechanisms of action of HDL and its altered vascular effects is therefore critical within the context of HDL-targeted therapies.

HDL dysfunction • Endothelial function • Atherosclerosis • CAD

Introduction

It was shown in multiple large prospective studies of cardiovascular risk factors that reduced plasma levels of HDL-cholesterol (HDL-C) are associated with an increased risk of coronary artery disease (CAD) (Castelli et al. 1986; Cullen et al. 1997; Di Angelantonio et al. 2009; Gordon et al. 1977; Sharrett et al. 2001). Multiple biological functions of HDL have been identified, whereby HDL may exert antiatherogenic effects (Annema and von Eckardstein 2013; Barter et al. 2004; Mineo et al. 2006; Rader 2006; Riwanto and Landmesser 2013), e.g., HDL from healthy subjects has been shown to directly promote endothelial antiapoptotic, anti-inflammatory, and antithrombotic effects (Mineo et al. 2006; Nofer et al. 2004; Rye and Barter 2008; Tall et al. 2008; Yuhanna et al. 2001). Accordingly, interventions to improve HDL-C levels and/or HDL function are being intensely evaluated as a potential therapeutic strategy to reduce cardiovascular risk. However, increasing evidence suggests that the endothelial and vascular effects of HDL are highly heterogeneous and vasoprotective properties of HDL are impaired in patients with diabetes, CAD, or chronic kidney dysfunction (Besler et al. 2011; Khera et al. 2011; Riwanto et al. 2013; Sorrentino et al. 2010).

Intriguingly, several recent clinical trials testing the effects of HDL-C-raising therapies have failed to demonstrate cardiovascular risk reduction in patients with CAD. The Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial testing the impact of the CETP inhibitor torcetrapib on clinical outcome showed increased risk of mortality and morbidity in patients at high risk for coronary events, despite a substantial increase of HDL-C levels (Barter et al. 2007). Dalcetrapib, another CETP inhibitor, modestly increased HDL-C levels, but the phase 3 trial dal-OUTCOMES study was terminated before completion to a lack of efficacy (Schwartz et al. 2012). More recently, the HPS2-THRIVE trial results showed that adding extended-release niacin/laropiprant, another HDL-cholesterol-raising agent, to statins did not reduce the risk of cardiovascular event (Haynes et al. 2013). Taken together, these observations strongly suggest that plasma HDL-C levels per se are not an optimal therapeutic target.

Of note, accumulating evidence suggests that the vascular effects of HDL can be highly heterogeneous and may turn dysfunctional. HDL loses potential antiatherosclerotic properties in patients with chronic inflammatory disorders, such as the antiphospholipid syndrome (Charakida et al. 2009), systemic lupus erythematosus and rheumatoid arthritis (McMahon et al. 2006), scleroderma (Weihrauch et al. 2007), metabolic syndrome (de Souza et al. 2008), diabetes (Persegol et al. 2006; Sorrentino et al. 2010), and CAD (Ansell et al. 2003; Besler et al. 2011; Riwanto et al. 2013). In a study of 189 patients with chronic kidney disease on hemodialysis, an impaired anti-inflammatory capacity of HDL was correlated with a poor clinical outcome (Kalantar-Zadeh et al. 2007). Furthermore, HDL isolated from subjects with type 1 or type 2 diabetes mellitus or abdominal obesity had reduced capacity to reverse the inhibition of aortic ring endotheliumdependent relaxation by oxLDL as compared to HDL from healthy control subjects (Persegol et al. 2006, 2007). Importantly, the heterogeneity of the vascular effects of HDL may be attributed to changes in the HDL-associated proteome and lipidome, i.e., changes in the amount and type of proteins and lipids bound to the HDL particle and also posttranslational modifications. In particular, HDL is known to be susceptible to modification in vitro by a variety of oxidants, such as metal ions, peroxyl and hydroxyl radicals, aldehydes, various myeloperoxidase (MPO)generated oxidants, lipoxygenase, phospholipase A2, elastase, nonenzymatic glycation, and homocysteinylation (Ferretti et al. 2006). These oxidative modifications may contribute to the generation of dysfunctional proinflammatory HDL.