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Qualitative analysis of oxidative modifications of apolipoprotein amino acid residues in in vivo-oxidized lipoprotein that is increased in patients with acute myocardial infarction

ABSTRACT: Oxidized low-density lipoprotein (oxLDL) is a known risk factor for atherogenesis. However, it is not clear what are the key components of oxLDL driving atherosclerosis.This study aimed to reveal structural features of oxLDL present in circulation of patients with acute myocardial infarction (AMI) and healthy subjects. Total LDL and HDL were separated from pooled sera prepared from 3-6 indivisuals of 25 AMI patients and plasma of seven healthy subjects using ultracentrifugation.When LDL was fractionated on an anion-exchange column, in vivo-oxLDL of AMI patients and healthy subjects, detected by the anti-oxidized phosphatidylcholine (oxPC) monoclonal antibody, was concentrated in electronegative LDL (LDL(-)) fraction. Surprisingly, LDL(-) fraction contained HDL-sized particles in addition to LDL observed using transmission electron microscopy. LC-MS/MS revealed this fraction contaned oxidized apolipoprotein A1 (apoA1) and all lysine residues of the oxidized apoA1 were modified by acrolein. The electronegative in vivo-oxLDL was immunologically purified from the LDL(-) fraction with an anti-oxPC monoclonal antibody, and LC-MS/MS analysis carried out to explore oxidatively modified peptides; but only a small number of acrolein-modified residues identified in the apoB. We propose that oxidized HDL interacts with in vivo-oxLDL that is involved in atherosclerosis.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Naoko Sawada

PROVIDER: PXD017957 | JPOST Repository | Tue Mar 10 00:00:00 GMT 2020

REPOSITORIES: jPOST

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Project description:Molecular mechanisms that influence susceptibility to multiple sclerosis are poorly understood. We conducted a gene expression study in healthy subjects that subsequently developed the disease. Gene expression profiles (HG U133A and A2, Affymetrix, 22,215 transcripts) of peripheral blood mononuclear cells were analyzed in 9 healthy subjects (mean age 19.8+1.1 years) up to 9 years (mean 5.1±1.2 years) before onset of MS (MS to be, MS2b), 11 age-, gender-, and origin-matched subjects that remained MS-free (MSf), and 31 clinically isolated syndrome (CIS) patients. Most informative genes (p<0.05) and significant biological processes were compared. 1051 genes (611 up-regulated, 440 down-regulated) were significantly different between MS2b and MSf subjects. MS2b signature was characterized by down-regulation of the nuclear receptor (NR) family genes including NR subfamily 4 group A member1 (NR4A1, p=0.01), member 3 (NR4A3, p=0.01), NR subfamily 2 group F member 2 (NR2F1, p=0.03) and vitamin D receptor (VDR, p=0.02), all known to be involved in T-cell regulation by apoptosis. Comparison between MS2b and CIS operating networks demonstrated evolution of the altered NR dependent apoptosis regulation. Decreased NR4A1 expression was verified at the mRNA and protein level in an independent cohort of 20 relapsing-remitting MS patients. The identified MS trait is associated with suppressed transcription of NR networks that leads to altered apoptosis of activated T cells and the development of clinical disease. MS2b subjects have already an ongoing process that eventually will lead to clinical disease and our finding are of importance as they suggest the possibility of early detection and prevention of MS. Keywords: disease state analysis Blood samples of healthy subjects that later developed MS (MS-to-be, MS2b, N=9) were identified and used for gene expression study. For each sample of MS2b subject, a sample of an age and gender matched subject that remained MS-free (MSf, N=11) was randomly selected. A cohort of 31 CIS patients who gave blood sample for gene expression analysis within 3 months of the onset of their first neurological event, was used for comparison with the MS2b gene expression signature. For establishment of the CIS gene expression signature, microarray data from 13 age- and sex- matched healthy subjects were used.

			Action	DRS
	S3.MGF.mgf	Mgf
	S3.raw.group	Raw
	S3_peptide.txt	Txt
	S3_protein.txt	Txt
	S4.MGF.mgf	Mgf

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Qualitative analysis of oxidative modifications of apolipoprotein amino acid residues in in vivo-oxidized lipoprotein that is increased in patients with acute myocardial infarction

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