International Journal of Cardiology 189 (2015) 15–17

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Editorial

Interaction between HDL and inflammation: When the good turns to be bad Nikolaos Papageorgiou MD PhD ⁎,1, Dimitris Tousoulis MD PhD FACC FESC 1st Cardiology Department, Athens University Medical School, Hippokration Hospital, Greece

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Article history: Received 5 February 2015 Accepted 17 March 2015 Available online 30 March 2015 Keywords: high-density lipoprotein atherosclerosis inflammation

Over the last decade, several studies have investigated the role of inflammation in atherosclerosis. Basic/experimental and clinical data have demonstrated that inflammation contributes to atherogenesis. In addition, such data have raised skepticism regarding the predictive role of inflammation for cardiovascular disease (CVD). On the other hand, studies have shown that high-density lipoprotein cholesterol (HDL) may hold an atheroprotective role, which turns to be atherogenic in states of increased inflammatory process. Likewise, it was shown that HDL isolated from patients with anti-phospholipid syndrome impaired nitric oxide bioavailability and increased superoxide production in cell cultures [1]. Moreover, a change in HDL protein load in states of increased inflammation and coronary artery disease (CAD) has been found [2]. Such results have raised questions regarding the lack of beneficial effects from agents which raise HDL levels. In the present journal issue, O'Neill et al. [3] aimed to determine the impact of low grade and acute inflammation on HDL function and structure. They reported that even minor alterations in systemic inflammation can impair the endothelial protective effects of HDL. Furthermore, these functional changes were independent of cholesterol efflux and were associated with remodeling of the HDL proteome. Interestingly, all measures of HDL's endothelial protective functions recovered with resolution of inflammation (Table 1).

⁎ Corresponding author at: Hippokration Hospital, Vasilissis Sofias 114, 115 28 Athens, Greece. E-mail address: [email protected] (N. Papageorgiou). 1 Equally contributed.

http://dx.doi.org/10.1016/j.ijcard.2015.03.411 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.

1. Anti-inflammatory effects of HDL Early 90s studies showed that HDL can possibly block experimental endotoxinemia, indicating that HDL binds lipopolysaccharide, thus lowering pro-inflammatory cytokine levels and improving survival rates. Although apolipoprotien A-I (ApoA-I) has a central role in the physical binding of LPS, the direct molecular effects of HDL on intracellular signaling may mediate the anti-inflammatory capacity of HDL. Considering that successful signal transduction is related to membrane microdomains with high concentrations of cholesterol and sphingolipids, it is possible that perturbation of these structures by HDL could explain the observed effects on cells of innate immunity [4]. It is also well known that the upregulation of adhesion molecules and release of chemoattractant proteins take part during the first steps of atherogenesis. Therefore, it was shown that HDL can inhibit cytokine-induced expression of adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1(ICAM-1), and Eselectin in cell cultures [5]. Of note, administration of apoA-I or HDL can downregulate the expression of adhesion molecules and monocyte infiltration in experimental models [6]. Additionally, HDL can attenuate the release of mediators such as chemoattractant protein-1 from endothelial cells (Table 2) [7]. 2. Detrimental effects of inflammation on HDL anti-inflammatory properties Inflammatory process can significantly change HDL composition with the incorporation of inflammatory markers such as the serum amyloid A1. In addition to this acute phase HDL turns to be unable to prevent LDL oxidation and adhesion molecule expression [8]. Ansell et al. [9] showed that the dysfunctional HDL in patients with CAD has reduced anti-oxidant activity. The impaired anti-inflammatory activity of HDL was also established by proteomic studies. Thus, several groups have demonstrated multiple changes in protein composition of HDL in patients with CAD [10]. Moreover, increased inflammatory process, as in patients with chronic kidney disease (CKD) and rheumatoid arthritis, can alter the functional capacity of HDL demonstrating that HDL was less potent in promoting cholesterol efflux [11,12]. More specifically, in CKD and psoriasis patients, compositional alterations were found and strong association between apoAI/phosphatidylcholine content and the cholesterol efflux capability of HDL was reported [11]. More

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Editorial

Table 1 Anti-atherogenic affects of high-density lipoprotein cholesterol. Anti-inflammatory Anti-thrombotic

Anti-oxidant Anti-apoptotic

Immunomodulatory Endothelium-related

-Decreased expression of adhesion molecules -Decreased adhesion of monocytes -Decreased activation of platelets -Decreased aggregation of platelets -Decreased generation of thrombin -Decreased oxidation of lipids -Decreased activation of caspases -Decreased apoptosis mediated by tumor necrosis factor alpha -Increased activation of Akt/Erk 1,2 -Decreased function of antigen presenting cells -Decreased activity of B&T cell receptors -Increased bioavailability of nitric oxide

Abbreviations: & :and; Akt: protein kinase B; Erk: extracellular-signal-regulated kinase.

recent studies have shown that HDL in CKD patients has a proinflammatory role by affecting cytokine network as well as adhesion molecule expression [13]. Awaili et al. [10], using proteomic analysis of HDL, found that SAA is enriched in patients with myocardial infarction implying a substitution of anti-inflammatory with pro-inflammatory HDL (Table 3). Also, enzymatic activity alterations may contribute to the antioxidative deficiency of HDL. Therefore, paraoxonase 1 (PON1) and lipoprotein-associated phospholipase A2 (LpPLA2) activities modified in HDL of patients with inflammatory diseases. More specifically, PON activity is reduced in CAD patients, CKD and rheumatoid arthritis, while LpPLA2 activity is augmented in CKD and psoriasis. Considering the fact that myeloperoxidase selectively induces HDL oxidation [14], HDL associated PON1 may be selectively inactivated. Interestingly, HDL from patients with either stable or unstable CAD had low PON1 activity and inhibited endothelial cell nitric oxide production [15]. In accordance, O'Neill et al. [3] showed that PON activity and nitric oxide bioavailability were reduced, while superoxide production was increased in patients with increased inflammation. In addition, there was an acute deterioration in HDL's endothelial protective function, without change in cholesterol efflux in the group with increased inflammation. The HDL function returned to baseline after resolution of inflammation.

Table 2 Therapeutic approaches raising high-density lipoprotein cholesterol. Type of therapy/target

Agents/modification

Non-pharmacological

-Increased exercise -Smoking cessation -Decreased alcohol intake -Statins -Fibrates -Niacin -Thiazolidinediones -Probucol-like agents

Established pharmacological

High-density lipoprotein functionality High-density lipoprotein composition High-density lipoprotein metabolism

High-density lipoprotein/apolipoprotein AI

-Infusion of ex-vivo delipidated high-density lipoprotein -ABC1 gene overexpression -Dalcetrabib -Anacetrabib -Endothelial lipase inhibitors -LCAT activators -Mutant ApoA-I -Plasma derived wild-type ApoA-I -Recombinant ApoA-I -Flavonoid derivatives -ApoA-I mimetic peptides

Abbreviations: ABC1: ATP-binding cassette transporter 1; LCAT: Lecithin—cholesterol acyltransferase; ApoA-I: apolipoprotein A1.

3. Concluding remarks — disappointment and complexity The inflammatory nature of atherosclerotic vascular disease has been extensively studied. Several studies have shown that the inflammatory process is a crucial process implicated in the initiation, progression and rupture of atherosclerotic plaque. Therefore, several studies have aimed to reduce inflammation so as to prevent or reduce the rate of cardiovascular events. The role of lipids is crucial in the formation of the atheromatous plaque and its rupture. Despite significant advances in treatment, specifically with the highly effective statin therapy, the majority of cardiovascular events are still not prevented. Data from epidemiological and translational studies demonstrated a strong inverse association between HDL cholesterol concentrations HDL or apoA-I levels with both CAD and its adverse events. Although the causal nature of this association has been questioned, HDL along with its major protein, apoA-I, have been shown to prevent and reverse atherosclerosis in animal models. Therefore, it was thought that raising HDL might be a therapeutic option in reducing cardiovascular events. However, recent clinical trials with drugs that raise HDL have been disappointing. Moreover, recent Mendelian randomization studies examining genetic variants which influence HDL levels suggest that these may not be causally linked to CAD development. These data underscore our incomplete understanding of the relationship between HDL and or apoA-I and CAD. Moreover, several studies have focused on the anti-inflammatory role of HDL. Further to this, it has been identified that apart from acute inflammation other chronic inflammatory conditions including cardiovascular disease may render HDL “dysfunctional” or pro-inflammatory. One potential mechanism that may contribute to impairment of HDL function is oxidative modification of the particle by myeloperoxidase which binds to HDL via a specific binding domain on apoA-I, promoting selective targeting of the lipoprotein in human plasma and atherosclerotic plaque for oxidative modification and a resultant loss of cholesterol efflux function. Strongly related to HDL is apoA-I. Apolipoprotein A-I is a major protein that is a component of high-density lipoprotein, or HDL cholesterol. Alterations of HDL by oxidation impair the capacity to promote cholesterol efflux from monocytes and macrophages and may result in a loss of antiinflammatory effects and a resulting change to a pro-inflammatory nature. Using phage-display affinity maturation, coupled with recombinant immunoglobulin engineering, A high affinity mono-clonal antibody (mAb) that specifically recognizes apoA1/HDL modified by the MPO/ H2O2/halide system was recently developed [16]. Using this antibody, they were able to identify that this oxidized apoA1 can be found in high abundance in atheromatous plaques and only a small amount can be found in the circulation possibly by diffusion out of the artery wall. It is therefore possible that quantification of this oxidized apoA1 in the circulation can serve as a gauge of molecular processes that impair apoA-I/HDL function in the artery wall. The disappointment arising from the discouraging HDL data has lead to more intensive research on LDL, which was forgotten in the last years. Therapeutic approaches such as the inhibition of PCSK9 seem to drive the lipid therapy towards this direction. Given the several controversies on HDL face and its complexity it becomes more evident that more careful clinical trials are needed to be determined, which HDL related therapeutic interventions may indeed exert anti-inflammatory/antiatherogenic effects. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. Acknowledgments None.

Editorial

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Table 3 High-density lipoprotein cholesterol, atherosclerosis and cardiovascular disease. Study

Population

Number of subjects

HDL-2

HDL-3

Alagona et al. [17] Sharrett et al. [18] Mora et al. [19] Williams et al. [20]

Asymptomatic subjects Healthy subjects Female subjects Healthy subjects

89 12.339 27.673 1905

Williams et al. [21]

CHD/controls

1905

Lamon-Fava et al. [22]

CHD

256

Associated inversely with IMT Lower for cases Relative to lowest quintile Lowest quartile of HDL2-mass predicted greater incident CHD Lowest HDL2-mass quartile increased the risk for total CHD and premature CHD Coronary atherosclerosis progression unrelated

Brown et al. [23]

CHD

160

No association with IMT Lower for cases No significance for medium and small size HDLs Lowest quartile of HDL3-mass predicted incident CHD Lowest HDL3-mass quartile increased the risk for total CHD and premature CHD Coronary atherosclerosis progression unrelated to changes. Greater progression for greater reductions. No association

Progression inversely related to medium to large size apoA-I only HDL and HDL2

Abbreviations: CHD: coronary heart disease; IMT: intima-media thickness; HDL: high-density lipoprotein; apo: apolipoprotein.

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Interaction between HDL and inflammation: When the good turns to be bad.

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