May-Zhang-jbc.RA117.001099.pdf

2019-06-12T18:40:39Z (GMT) by Jiansheng Huang
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Cardiovascular disease (CVD) risk depends

on HDL function, not HDL-cholesterol

(HDL-C). Isolevuglandins (IsoLGs) are lipid dicarbonyls

that react with lysine residues of proteins

and phosphatidylethanolamine. IsoLG adducts

are elevated in atherosclerosis. The consequences

of IsoLG modification of HDL have not

been studied. We hypothesized that IsoLG modification

of apoA-I deleteriously alters HDL

function. We determined the effect of IsoLG on

HDL structure-function, and whether pentylpyridoxamine

(PPM), a dicarbonyl scavenger,

can preserve HDL function. IsoLG-adducts

in HDL derived from patients with familial hypercholesterolemia

(n=10, 233.4±158.3 ng/mg)

were found to be significantly higher than in

healthy controls (n=7, 90.1±33.4 pg/mg protein).

Further, HDL exposed to myeloperoxidase had

elevated IsoLG-lysine adducts (5.7 ng/mg protein)

compared to unexposed HDL (0.5 ng/mg

protein). Preincubation with PPM reduced

IsoLG-lysine adducts by 67%, while its inactive

analogue pentylpyridoxine (PPO) did not. Addition

of IsoLG produced apoA-I and apoA-II

crosslinks beginning at 0.3 molar equivalents

IsoLG per mol apoA-I (0.3 eq.), while succinylaldehyde

and 4-hydroxynonenal (HNE) required

10 and 30 eq. IsoLG increased HDL size, generating a subpopulation of 16-23 nm. 1 eq.

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IsoLG decreased HDL-mediated 3H-cholesterol

efflux from macrophages via ABCA1, which

corresponded to a decrease in HDL-apoA-I exchange

from 47.4% to only 24.8%. This suggests

that IsoLG inhibits apoA-I from disassociating

from HDL to interact with ABCA1. Addition of

0.3 eq IsoLG ablated HDL’s ability to inhibit

LPS-stimulated cytokine expression by macrophages,

and increased IL-1β expression by 3.5-

fold. The structural-functional effects were partially

rescued with PPM scavenging.

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generating a subpopulation of 16-23 nm. 1 eq.

IsoLG decreased HDL-mediated 3H-cholesterol

efflux from macrophages via ABCA1, which

corresponded to a decrease in HDL-apoA-I exchange

from 47.4% to only 24.8%. This suggests

that IsoLG inhibits apoA-I from disassociating

from HDL to interact with ABCA1. Addition of

0.3 eq IsoLG ablated HDL’s ability to inhibit

LPS-stimulated cytokine expression by macrophages,

and increased IL-1β expression by 3.5-

fold. The structural-functional effects were partially

rescued with PPM scavenging.