Apolipoprotein CIII: a link between hypertriglyceridemia and vascular dysfunction?

The incidence of obesity-associated disorders, such as type 2 diabetes and the metabolic syndrome, is continuously increasing worldwide.1 These disorders are characterized by abnormalities in glucose and lipid metabolism, putting patients at increased risk for macroand microvascular complications.2 Although statin treatment, which primarily targets elevated plasma low-density lipoprotein (LDL)-cholesterol levels, lowers cardiovascular morbidity and mortality in patients with type 2 diabetes,3 it is increasingly clear that a significant residual cardiovascular risk remains in these patients,3–5 which is partly attributable to the typical atherogenic lipoprotein profile (ALP) characterized by hypertriglyceridemia and low high-density lipoprotein (HDL)-cholesterol concentrations.6 Post hoc analysis of statin trials, such as PROVE-IT TIMI 22, have identified plasma triglycerides as a determinant of cardiovascular risk in patients achieving LDL-cholesterol goals.5 Plasma triglyceride concentrations are determined by the balance between clearance/uptake and production of triglyceride (TG)-rich lipoproteins (7). Dysregulation of this balance results in the development of hypertriglyceridemia.7 Triglycerides in very-low-density lipoproteins (VLDL) and chylomicrons are hydrolyzed by lipoprotein lipase, thus allowing their conversion to remnant and subsequently to LDL particles. This process is controlled by specific apolipoprotein (apo) constituents, such as apoCII and apoAV, which facilitate TG-rich lipoprotein clearance/lipolysis, whereas apoCIII delays it.8 ApoCIII is a 79-aa glycoprotein synthesized in the liver and the intestine and a major component of the apoBcontaining TG-rich lipoproteins and HDL.8 Plasma apoCIII levels are positively correlated with plasma triglycerides over the entire spectrum from normoto hypertriglyceridemia.8 ApoCIII deficiency results in hypertriglyceridemia both in humans and mice, whereas overexpression of apoCIII in mice results in hypertriglyceridemia.8–10 The functions of apoCIII in lipoprotein metabolism are multiple.8 First, apoCIII inhibits lipoprotein lipase activity and hence delays lipoprotein triglyceride lipolysis.8 Second, apoCIII impairs glycosaminoglycan–lipoprotein interactions11 and receptor-mediated uptake of TG-rich remnant lipoproteins.8 Moreover apoCIII stimulates VLDL assembly and secretion.8 In the Cholesterol and Recurrent Events (CARE) clinical trial, apoCIIIcontaining apoB lipoproteins (LpB:CIII) emerged as an independent predictor of recurrent coronary events.12 More recently, a series of articles have identified novel, unexpected functions of apoCIII, which exerts direct proatherogenic activities resulting in endothelial dysfunction and monocyte activation and adhesion. ApoCIII-enriched lipoproteins induce endothelial cell expression of the adhesion molecules vascular cell adhesion molecule-1 and intercellular adhesion molecule-1.13 ApoCIII also impairs insulin signaling in vitro and in vivo in endothelial cells, leading to a decrease of nitric oxide (NO) production and an increase of endothelin-1 synthesis and secretion, effects that enhance vasoconstriction.14 Moreover, LpB:CIII particles increase protein kinase C – and RhoA-mediated -integrin activation in monocytes.15 Finally, apoCIII-mediated nuclear factor (NF)B activation in monocytes further enhances the inflammatory response.16 All these actions result in enhanced monocyte adhesion to endothelial cells. Altogether, these results identified a direct vascular activity of apoCIII to induce endothelial dysfunction. However, the molecular and cellular mechanisms involved in these responses to apoCIII were unresolved. In this issue of Circulation Research, Kawakami et al17 identify a direct molecular target of apoCIII. The authors demonstrate that apoCIII-induced monocyte activation is mediated by Toll-like receptor (TLR)2 activation in vitro and in vivo. TLRs were initially identified as major sensors of the innate immune response (for instance in case of microbial infection). TLRs are principal sensors of the innate immune system and provide a molecular link between infection, inflammation, and, more recently, atherosclerosis development.18 The authors show that incubation of human THP-1 monocytes or human peripheral blood monocytes with a blocking antibody against TLR2, but not TLR4, reduces apoCIII-induced monocyte adhesion to HUVEC cells. Incubation of monocytes with the TLR2 antibody also reduced protein kinase C and NFB activation and induction of 1-integrin expression by apoCIII. Most interestingly, the authors showed by a combination of in vitro and in cellulo experiments that apoCIII binds directly to TLR2. Moreover, overexpression of TLR2 enhanced apoCIII-mediated activation of NFB and induction of 1-integrin expression. ApoCIII induced the same pathways in monocytes isolated from wild type, but not from TLR2-deficient mice. Finally, intravenous administration of apoCIII-rich VLDL, but not apoCIII-deficient VLDL, in wild-type mice led to an increase The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From Institut Pasteur de Lille; INSERM; and Université de Lille 2, Faculté des Sciences Pharmaceutiques et Biologiques et Faculté de Médecine, Lille, France. Correspondence to Bart Staels, Université de Lille 2, Faculté des Sciences Pharmaceutiques et Biologiques et Faculté de Médecine, Lille F-59006, France. E-mail [email protected] (Circ Res. 2008;103:1348-1350.) © 2008 American Heart Association, Inc.