High-Density Lipoprotein Proteomics: Identifying New Drug Targets and Biomarkers by Understanding Functionality

Gordon, Scott M.; Durairaj, Anita; Lu, Jason; Davidson, W. Sean

doi:10.1007/s12170-009-0069-9

Cited by 33 publications

(29 citation statements)

References 46 publications

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“…The enrichment of distinct proteins in HDLs in various diseases states evolves as an important determinant for associations between HDL function and cardiovascular risk (16,30,45). Our improved understanding of the composition of HDLs can enable pharmacologic attempts in manipulating HDL composition and function to reduce cardiovascular risk.…”

Section: Discussionmentioning

confidence: 99%

“…HDLs are a family of heterogeneous particles that vary 4-fold in cholesterol content (28,29) and carry a protein cargo of .50 different proteins (30,31). The protein composition of HDLs emerges as important determinant when investigating the association between HDL function or concentration and CVD (30,32).…”

Section: Introductionmentioning

confidence: 99%

“…The protein composition of HDLs emerges as important determinant when investigating the association between HDL function or concentration and CVD (30,32). For example, individual proteins were found enriched or depleted in HDLs from patients with diseases that bear major cardiovascular risks, such as ESRD, coronary artery disease, or rheumatoid arthritis (25,26,31,(33)(34)(35).…”

Section: Introductionmentioning

confidence: 99%

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Quantification of HDL Proteins, Cardiac Events, and Mortality in Patients with Type 2 Diabetes on Hemodialysis

Kopecky¹,

Genser

Drechsler³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Impairment of HDL function has been associated with cardiovascular events in patients with kidney failure. The protein composition of HDLs is altered in these patients, presumably compromising the cardioprotective effects of HDLs. This post hoc study assessed the relation of distinct HDL-bound proteins with cardiovascular outcomes in a dialysis population.Design, setting, participants, & measurements The concentrations of HDL-associated serum amyloid A (SAA) and surfactant protein B (SP-B) were measured in 1152 patients with type 2 diabetes mellitus on hemodialysis participating in The German Diabetes Dialysis Study who were randomly assigned to double-blind treatment of 20 mg atorvastatin daily or matching placebo. The association of SAA(HDL) and SP-B(HDL) with cardiovascular outcomes was assessed in multivariate regression models adjusted for known clinical risk factors.Results High concentrations of SAA(HDL) were significantly and positively associated with the risk of cardiac events (hazard ratio per 1 SD higher, 1.09; 95% confidence interval, 1.01 to 1.19). High concentrations of SP-B(HDL) were significantly associated with all-cause mortality (hazard ratio per 1 SD higher, 1.10; 95% confidence interval, 1.02 to 1.19). Adjustment for HDL cholesterol did not affect these associations. ConclusionsIn patients with diabetes on hemodialysis, SAA(HDL) and SP-B(HDL) were related to cardiac events and all-cause mortality, respectively, and they were independent of HDL cholesterol. These findings indicate that a remodeling of the HDL proteome was associated with a higher risk for cardiovascular events and mortality in patients with ESRD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quantification of HDL Proteins, Cardiac Events, and Mortality in Patients with Type 2 Diabetes on Hemodialysis

Kopecky¹,

Genser

Drechsler³

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…Furthermore, two-dimensional electrophoresis studies by Asztalos and colleagues (18), as well as our own work (11,19), strongly support the concept that certain apolipoproteins segregate among different HDL particles. These observations present the intriguing possibility that the phospholipids of HDLs act as an organizing platform that facilitates the assembly of specific protein complexes (20). Such subspecies could have important functional implications in the context of CVD protection, inflammation, or even innate immune function.…”

mentioning

confidence: 99%

Multi-dimensional Co-separation Analysis Reveals Protein–Protein Interactions Defining Plasma Lipoprotein Subspecies

Gordon

Deng

Tomann

et al. 2013

Molecular & Cellular Proteomics

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The distribution of circulating lipoprotein particles affects the risk for cardiovascular disease (CVD) in humans. Lipoproteins are historically defined by their density, with low-density lipoproteins positively and high-density lipoproteins (HDLs) negatively associated with CVD risk in large populations. However, these broad definitions tend to obscure the remarkable heterogeneity within each class. Evidence indicates that each class is composed of physically (size, density, charge) and compositionally (protein and lipid) distinct subclasses exhibiting unique functionalities and differing effects on disease. HDLs in particular contain upward of 85 proteins of widely varying function that are differentially distributed across a broad range of particle diameters. We hypothesized that the plasma lipoproteins, particularly HDL, represent a continuum of phospholipid platforms that facilitate specific protein-protein interactions. To test this idea, we separated normal human plasma using three techniques that exploit different lipoprotein physicochemical properties (gel filtration chromatography, ionic exchange chromatography, and preparative isoelectric focusing). We then tracked the co-separation of 76 lipid-associated proteins via mass spectrometry and applied a summed correlation analysis to identify protein pairs that may co- Lipoproteins are circulating emulsions of protein and lipid that play important roles, both positive and negative, in cardiovascular disease (CVD).1 Historically defined by their density as separated by ultracentrifugation, the major lipoprotein classes include the neutral lipid ester-rich very low-density and low-density lipoproteins (VLDLs and LDLs, respectively), which function to transport triglyceride and cholesterol from the liver to the peripheral tissues. Significant epidemiological evidence, in vitro studies, animal experiments, and human clinical trials have shown that high-LDL cholesterol is a bona fide causative factor in CVD (1). In contrast, protein-and phospholipid-rich high-density lipoproteins (HDLs) are thought to mediate the reverse transport of cholesterol from the periphery to the liver for catabolism and to perform anti-oxidative and anti-inflammatory functions (reviewed in Refs. 2 and 3). A host of human epidemiology and animal studies indicate that HDLs are atheroprotective (4). However, recent clinical trials of therapeutics that generically raise HDL, at least as measured by its cholesterol levels, have failed to confer the expected CVD protections (5-7).Although these traditional density-centric definitions have been used for nearly 40 years, accumulating evidence indicates that they are not particularly reflective of lipoprotein compositional and functional complexity. With respect to most physical traits (size, charge, lipid content, protein content, etc.), one can demonstrate significant heterogeneity within each density class. This suggests that particle subspecies exist with unique functions and effects on disease. For example, LDL can be resolved into large,...

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“…[293][294][295] Recent proteomic analysis of high density lipoprotein-cholesterol (HDL) particles, which are inversely correlated with the incidence of CVD, have revealed new HDL-associated proteins and suggested that the particles of different composition may have different cardioprotective activity. 296,297 Plasma proteomic approach has been applied to identify new biomarkers in acute myocardial infarction (AMI). Serum levels of apolipoprotein J (ApoJ) have been downregulated and have been less glycosylated in patients with newonset AMI compared to control individuals.…”

Section: Proteomics and Metabolomicsmentioning

confidence: 99%

The Path to Personalized Cardiovascular Medicine

Marı́n-Garcı́a

2014

Post-Genomic Cardiology

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High-Density Lipoprotein Proteomics: Identifying New Drug Targets and Biomarkers by Understanding Functionality

Cited by 33 publications

References 46 publications

Quantification of HDL Proteins, Cardiac Events, and Mortality in Patients with Type 2 Diabetes on Hemodialysis

Quantification of HDL Proteins, Cardiac Events, and Mortality in Patients with Type 2 Diabetes on Hemodialysis

Multi-dimensional Co-separation Analysis Reveals Protein–Protein Interactions Defining Plasma Lipoprotein Subspecies

The Path to Personalized Cardiovascular Medicine

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