HDL’s Protein Cargo
2013; Lippincott Williams & Wilkins; Volume: 127; Issue: 8 Linguagem: Inglês
10.1161/circulationaha.112.000889
ISSN1524-4539
Autores Tópico(s)Lipoproteins and Cardiovascular Health
ResumoHomeCirculationVol. 127, No. 8HDL's Protein Cargo Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHDL's Protein CargoFriend or Foe in Cardioprotection? Jay W. Heinecke, MD Jay W. HeineckeJay W. Heinecke From the Department of Medicine, University of Washington, Seattle, WA. Originally published26 Feb 2013https://doi.org/10.1161/CIRCULATIONAHA.112.000889Circulation. 2013;127:868–869Low levels of high-density lipoprotein (HDL) particles were first linked to increased risk of cardiovascular disease (CVD) >40 years ago.1 Because analytic ultracentrifugation, the method used for those pioneering studies, is complex and time consuming, clinical investigators began to use HDL cholesterol (HDL-C) as a surrogate measure for HDL concentration. Clinical, epidemiological, and genetic studies provide robust evidence that low HDL-C levels associate with clinically significant CVD.2 Moreover, atherosclerosis increases markedly in hypercholesterolemic mice deficient in apolipoprotein (apoA)-I,3 the major HDL protein, whereas overexpression of human apoA-I dramatically retards atherosclerosis in hypercholesterolemic mice.4 Many lines of evidence indicate that apoA-I and HDL promote cholesterol efflux from macrophages, a key step in atherogenesis.5 Taken together, these findings provide strong evidence that apoA-I plays a key role in HDL's cardioprotective activities.Article see p 891These observations have triggered intense interest in targeting HDL-C for therapeutic intervention, because lowering low-density lipoprotein (LDL) levels with statins leaves a large residual risk in CVD subjects. However, several lines of evidence suggest that the association between HDL-C levels and CVD status is not a causal relationship and that elevating HDL-C is not necessarily therapeutic.6,7 For example, genetic variations that only affect HDL-C levels do not markedly alter CVD risk. Also, trials of several drugs that elevate HDL-C levels, such as cholesteryl ester transfer protein inhibitors and niacin, were terminated prematurely because of predicted lack of clinical benefit. Moreover, certain genetically engineered deficiencies in proteins involved in HDL metabolism greatly increase both HDL-C levels and atherosclerosis in mice,8 indicating that HDL-C does not necessarily reflect the propensity for atherosclerosis in animals or humans. Therefore, quantifying HDL-C may be a poor way to assess cardioprotection.7HDL is a family of particles that range in diameter from 8 nm to 12 nm and vary 4-fold in cholesterol content.9,10 Protein–protein interactions may be a major factor driving the assembly of specific kinds of particles, because >75% of HDL's surface is covered by proteins,10 not phospholipids or cholesterol. Two major components, apoA-I and apoA-II, account for the majority of HDL's protein mass (70% and 20%, respectively). Low levels of other apolipoproteins, such as apoE and apoC, are also present. However, mass spectrometric–based proteomic studies demonstrate that human HDL carries >50 other proteins,11,12 many of which are not implicated in lipid metabolism. It is therefore likely that each individual HDL particle carries ≥1 protein distinct from apoA-I and apoA-II. Unexpectedly, many HDL proteins are linked to the acute-phase response, the complement system, and protease inhibition,11 raising the possibility that the HDL proteome has anti-inflammatory as well as antiatherogenic properties.In this issue of Circulation, Riwanto et al13 demonstrate that HDL isolated from apparently healthy humans inhibits endothelial cell apoptosis both in cultured cells and a mouse model of hypercholesterolemia. The antiapoptotic pathway involves activation of PI3K/Akt and upregulation of the apoptotic protein Bcl-xL. In striking contrast, HDL isolated from stable CVD subjects or acute coronary syndrome subjects failed to inhibit apoptosis. Instead, it triggered activation of the p38-MAPK pathway and expression of the proapoptotic protein tBid. Proteomic and biochemical analyses showed that levels of clusterin, an anti-inflammatory protein, were reduced whereas levels of apoC-III, which inhibits triglyceride breakdown, were elevated in HDL from the CVD subjects. Moreover, in vitro studies demonstrated that an antibody to clusterin blocked the antiapoptotic effect of HDL from healthy subjects, and an antibody to apoC-III blocked the proapoptotic effect of HDL from CVD subjects. These exciting observations raise the possibility that certain proteins in HDL play previously unsuspected roles in regulating endothelial cell apoptosis.13 This action might be centrally important for preventing endothelial cell dysfunction and blocking multiple key steps in atherogenesis.The observations of Riwanto et al13 support the proposal that inflammation can generate dysfunctional forms of HDL that lack the normal cardioprotective properties or even become detrimental.14 They also identify a specific mechanism involving pro- and antiapoptotic proteins of the Bcl family.13 Moreover, clusterin is greatly enriched in a specific HDL subpopulation that carries phospholipid transfer protein.15 Genetic studies indicate that increased phospholipid transfer protein activity associates with increased HDL-C but increased CVD risk,16 again supporting the notion that HDL-C does not necessarily capture HDL's cardioprotective effects. In 2 independent populations, separating HDL-C according to its content of apoC-III identified 2 types of HDL with opposing associations with risk of CHD, suggesting that apoC-III is atherogenic in humans.17 Taken together, these observations suggest that some HDL proteins increase the risk for CVD whereas others decrease it, and that those effects are independent of HDL-C and perhaps apoA-I.In future studies it will be critical to address a number of issues. First, it will be important to replicate the current study in larger numbers of subjects and other populations. Second, it will be of interest to determine whether a specific subpopulation of HDL accounts for the lipoprotein's antiapoptotic effects and to identify the factors that control HDL's content of clusterin and apoC-III. It is noteworthy that low levels of HDL-clusterin, which inhibited apoptosis of cultured endothelial cells in the Riwanto studies, have been found in humans with insulin resistance, a major risk factor for type 2 diabetes mellitus and premature CVD.18 Third, it will be necessary to identify the factors that regulate expression of pro- and antiatherogenic proteins secreted by the liver, the likely source of many proteins that bind to HDL. Finally, recent studies demonstrate that aggressive lipid-lowering therapy remodels the HDL proteome.19 It will be critical to determine how established and proposed lipid therapies alter the protein composition of HDL and to establish whether such changes associate with clinical benefit.It is essential to develop new metrics for assessing HDL's cardioprotective effects. One diagnostic approach might be the cholesterol efflux assay, as serum HDL's capacity to promote cholesterol efflux from macrophages associates strongly and negatively with CVD status in 2 different human populations.20 That association is independent of HDL-C and apoA-I levels. Another might be based on the antiapoptotic activity of HDL uncovered by Riwanto et al. Although cell-based assays are technically demanding and therefore unlikely to be widely applicable to clinical studies, they might lead to quantitative, high-throughput assays that do not rely on HDL-C levels. They should also be useful in basic studies that exploit the links between dysfunctional HDL and CVD to improve treatment for the disorder.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Jay Heinecke, MD, UW Medicine SLU, 850 Republican St, Box 358055, Seattle, WA 98109. 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February 26, 2013Vol 127, Issue 8 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.112.000889PMID: 23439444 Originally publishedFebruary 26, 2013 KeywordsEditorialsatherosclerosisPDF download Advertisement SubjectsCell Biology/Structural BiologyCell Signaling/Signal TransductionEndothelium/Vascular Type/Nitric OxidePathophysiology
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