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HDL proteomics: pot of gold or Pandora’s box?
Muredach P. Reilly1 and Alan R. Tall2
1Cardiovascular Institute, Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA. 2Division of Molecular Medicine, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
Address correspondence to: Muredach P. Reilly, Cardiovascular Institute, University of Pennsylvania Medical Center, 909 BRB 2/3, 421 Curie Blvd., Philadelphia, Pennsylvania 19104-6160, USA. Phone: (215) 573-1214; Fax: (215) 573-2094; E-mail: muredach@itmat.gcrc.upenn.edu.
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1Cardiovascular Institute, Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA. 2Division of Molecular Medicine, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
Address correspondence to: Muredach P. Reilly, Cardiovascular Institute, University of Pennsylvania Medical Center, 909 BRB 2/3, 421 Curie Blvd., Philadelphia, Pennsylvania 19104-6160, USA. Phone: (215) 573-1214; Fax: (215) 573-2094; E-mail: muredach@itmat.gcrc.upenn.edu.
Find articles by Tall, A. in: PubMed | Google Scholar
Published March 1, 2007 - More info
J Clin Invest. 2007;117(3):595–598. https://doi.org/10.1172/JCI31608.
© 2007 The American Society for Clinical Investigation
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Abstract
HDL lowers the risk for atherosclerotic cardiovascular disease by promoting cholesterol efflux from macrophage foam cells. However, other antiatherosclerotic properties of HDL are poorly understood. To test the hypothesis that the lipoprotein carries proteins that might have novel cardioprotective activities, we used shotgun proteomics to investigate the composition of HDL isolated from healthy subjects and subjects with coronary artery disease (CAD). Unexpectedly, our analytical strategy identified multiple complement-regulatory proteins and a diverse array of distinct serpins with serine-type endopeptidase inhibitor activity. Many acute-phase response proteins were also detected, supporting the proposal that HDL is of central importance in inflammation. Mass spectrometry and biochemical analyses demonstrated that HDL3 from subjects with CAD was selectively enriched in apoE, raising the possibility that HDL carries a unique cargo of proteins in humans with clinically significant cardiovascular disease. Collectively, our observations suggest that HDL plays previously unsuspected roles in regulating the complement system and protecting tissue from proteolysis and that the protein cargo of HDL contributes to its antiinflammatory and antiatherogenic properties.
Authors
Tomas Vaisar, Subramaniam Pennathur, Pattie S. Green, Sina A. Gharib, Andrew N. Hoofnagle, Marian C. Cheung, Jaeman Byun, Simona Vuletic, Sean Kassim, Pragya Singh, Helen Chea, Robert H. Knopp, John Brunzell, Randolph Geary, Alan Chait, Xue-Qiao Zhao, Keith Elkon, Santica Marcovina, Paul Ridker, John F. Oram, Jay W. Heinecke
The inverse relationship between plasma HDL-cholesterol (HDL-C) levels and atherosclerotic cardiovascular disease (CVD) provides the epidemiological basis for the widely accepted hypothesis that HDL is atheroprotective. Despite intense research, the underlying mechanisms of HDL atheroprotection remain incompletely understood. Indeed, recent clinical trials (1, 2) indicate the complexity of HDL physiology and the challenges in developing HDL therapies. HDL function, and benefit with a specific therapy, may depend more on the molecular mechanism driving increases in HDL-C than on the absolute level of HDL-C (3). Some interventions that raise HDL-C levels may have no benefit and even promote atherosclerosis (4), while other therapies may reduce CVD without actually changing HDL-C levels (1). Overall, the epidemiological evidence suggests that the majority of mechanisms that result in higher HDL-C levels in vivo will provide atheroprotection; the question is how to identify such targets. This requires a shift in mindset toward assessing HDL in terms of its atheroprotective functions rather than just levels of cholesterol and its main apoprotein, APOAI.
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Measures of HDL atheroprotective function and the HDL proteome
We continue to have limited insight into the precise mechanisms of HDL atheroprotection, in part, due to our inability to assess HDL functions in vivo. Although several measures of HDL particles, composition, and function exist (Table 1), there are no tractable methods for assessing RCT in humans, and simple, reliable, and reproducible assays of HDL antiinflammatory functions are lacking. In this setting, recent HDL proteomic studies may provide novel insights into HDL physiology and the potential for development of bioassays of HDL function, although such studies are in their infancy (16, 19, 22–24).
In this issue, Vaisar et al. present the largest and most comprehensive mass spectrometry–based study to date of the HDL proteome (16). Arguably, the most striking aspect of these early studies is not just the diversity of the HDL proteins and peptides (16, 19) identified but also the overrepresentation of proteins involved in several non–lipid transport functions, including the acute-phase response, complement regulation, proteolysis, and coagulation (16, 19, 22, 24) (Supplemental Table 1; supplemental material available online with this article; doi:10.1172/JCI31608DS1), suggesting novel HDL functions. Although convincing evidence of functional roles for HDL in these processes is limited, past and emerging studies have shown that HDL and/or APOAI can attenuate response to experimental endotoxemia (17), inhibit complement activation (25), and inhibit platelet activation, serpins, and thrombosis (26).
The current study (16) is notable for examining a large human sample (albeit including only 33 subjects), comparing HDL proteins isolated from the plasma of healthy controls with HDL proteins from patients with CAD (n = 7) and with HDL isolated from human atherosclerotic plaques. Importantly, semiquantitative peptide counting linked to appropriate statistical methodologies was applied to assess relative protein abundance and provided evidence that HDL in CAD is enriched in APOE and complement components 3 and 4, protein changes that may relate to both RCT and antiinflammatory functions. The observation that the plasma HDL in CAD contains a subset of proteins found on HDL in atherosclerotic plaques requires validation but implies that the HDL proteome can provide a window into plaque activity. Whether such protein changes, and which ones, are measures of HDL atheroprotective functions has yet to be determined.
The degree of variation across studies in the number and identity of proteins associated with HDL (Supplemental Table 1; refs. 16, 19, 22–24) raises some concerns. This is likely related to technical differences in HDL isolation and subsequent methodology and highlights the need for technical standardization and rigorous external validation.
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