Dataset Information

Human HDL 2D-LC-MS/MS

ABSTRACT: Besides modulation of reverse cholesterol transport, high density lipoprotein (HDL) is able to modulate vascular function by stimulating endothelial nitric oxide synthase. Recently, it could be documented that this function of HDL was significantly impaired in patients with chronic heart failure (CHF). We investigated the impact of HDL proteome in CHF patients. Therefore, HDL was isolated from 5 controls (HDLhealthy) and 5 CHF patients of NYHA-class IIIb (HDLCHF). Proteome of HDL particles was performed by two-dimensional liquid chromatography mass spectrometry (SCX/RP LC-MS/MS). In total, we identified 494 distinct proteins, of which 107 proteins were commonly found in both groups (HDLCHF and HDLhealthy) indicating a high inter-subject variability across HDL particles. Several important proteins (e.g. ITGA2, APBA1 or A2M) varied in level. Functional analysis revealed intracellular regulated pathways. A minor proportion of bacteria-derived proteins were identified in the analyzed HDL-particles. The extension of the list of HDL-associated proteins allows beside their mere description new insights into alterations in HDL function in diseases. In addition, the detection of bacterial proteins bound to HDL will broaden our view of HDL not only as a cholesterol carrier but also as a carrier of several regulating proteins and even bacterial proteins.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Uwe V�lker

PROVIDER: MSV000080857 | MassIVE | Sat Apr 01 00:29:00 BST 2017

SECONDARY ACCESSION(S): PXD002977

REPOSITORIES: MassIVE

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Publications

Proteome profiles of HDL particles of patients with chronic heart failure are associated with immune response and also include bacteria proteins.

Oberbach Andreas A Adams Volker V Schlichting Nadine N Heinrich Marco M Kullnick Yvonne Y Lehmann Stefanie S Lehmann Sven S Feder Stefan S Correia Joao Carlos JC Mohr Friedrich-Wilhelm FW Völker Uwe U Jehmlich Nico N

Clinica chimica acta; international journal of clinical chemistry 20151211

Besides modulation of reverse cholesterol transport, high density lipoprotein (HDL) is able to modulate vascular function by stimulating endothelial nitric oxide synthase. Recently, it could be documented that this function of HDL was significantly impaired in patients with chronic heart failure (CHF). We investigated alterations in the HDL proteome in CHF patients. Therefore, HDL was isolated from 5 controls (HDLhealthy) and 5 CHF patients of NYHA-class IIIb (HDLCHF). Proteome analysis of HDL p ...[more]

PMID: 26688386

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Project description:Despite considerable progress understanding genes that affect the HDL particle, its function, and cholesterol content, genes identified to date explain only a small percentage of the genetic variation. We used N-ethyl-N-nitrosourea mutagenesis in mice to discover novel genes that affect HDL cholesterol levels. Two mutant lines (Hlb218 and Hlb320) with low HDL cholesterol levels were established. Causal mutations in these lines were mapped using linkage analysis: For line Hlb218 within a 12 Mbp region on Chr 10; and for line Hlb320 within a 17 Mbp region on Chr 7. High-throughput sequencing of Hlb218 liver RNA identified a mutation in Pla2g12b. The transition of G to A leads to a cysteine to tyrosine change and most likely causes a loss of a disulfide bridge. Microarray analysis of Hlb320 liver RNA showed a 7-fold downregulation of Hpn; sequencing identified a mutation in the 3M-bM-^@M-2 splice site of exon 8. Northern blot confirmed lower mRNA expression level in Hlb320 and did not show a difference in splicing, suggesting that the mutation only affects the splicing rate. In addition to affecting HDL cholesterol, the mutated genes also lead to reduction in serum non-HDL cholesterol and triglyceride levels. Despite low HDL cholesterol levels, the mice from both mutant lines show similar atherosclerotic lesion sizes compared to control mice. These new mutant mouse models are valuable tools to further study the role of these genes, their affect on HDL cholesterol levels, and metabolism. Mutant mice were generated as part of The Jackson LaboratoryM-bM-^@M-^Ys Heart, Lung, Blood, and Sleep Disorder Mutagenesis Program by treating male C57BL/6J (B6) mice with N-ethyl-N-nitrosourea (ENU). Third generation (G3) mice were phenotyped to ensure capture of both dominant and recessive mutations. Two unique G3 animals with low HDL cholesterol levels were then used to establish new inbred lines (Hlb218 and Hlb320) by mating them with B6 mice and intercrossing the offspring with low HDL cholesterol for 7 generations. Livers from 3 Hlb218, 3 Hlb320 males, and 6 B6 male controls were obtained for gene expression analysis. The samples were randomized over Illumina Mouse-6 Expression 1.1 BeadChips .