May-Zhang-jbc.RA117.001099.pdf HuangJiansheng 2019 p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 11.0px Times} <p>Cardiovascular disease (CVD) risk depends</p> <p>on HDL function, not HDL-cholesterol</p> <p>(HDL-C). Isolevuglandins (IsoLGs) are lipid dicarbonyls</p> <p>that react with lysine residues of proteins</p> <p>and phosphatidylethanolamine. IsoLG adducts</p> <p>are elevated in atherosclerosis. The consequences</p> <p>of IsoLG modification of HDL have not</p> <p>been studied. We hypothesized that IsoLG modification</p> <p>of apoA-I deleteriously alters HDL</p> <p>function. We determined the effect of IsoLG on</p> <p>HDL structure-function, and whether pentylpyridoxamine</p> <p>(PPM), a dicarbonyl scavenger,</p> <p>can preserve HDL function. IsoLG-adducts</p> <p>in HDL derived from patients with familial hypercholesterolemia</p> <p>(n=10, 233.4±158.3 ng/mg)</p> <p>were found to be significantly higher than in</p> <p>healthy controls (n=7, 90.1±33.4 pg/mg protein).</p> <p>Further, HDL exposed to myeloperoxidase had</p> <p>elevated IsoLG-lysine adducts (5.7 ng/mg protein)</p> <p>compared to unexposed HDL (0.5 ng/mg</p> <p>protein). Preincubation with PPM reduced</p> <p>IsoLG-lysine adducts by 67%, while its inactive</p> <p>analogue pentylpyridoxine (PPO) did not. Addition</p> <p>of IsoLG produced apoA-I and apoA-II</p> <p>crosslinks beginning at 0.3 molar equivalents</p> <p>IsoLG per mol apoA-I (0.3 eq.), while succinylaldehyde</p> <p>and 4-hydroxynonenal (HNE) required</p> <p>10 and 30 eq. IsoLG increased HDL size, generating a subpopulation of 16-23 nm. 1 eq.</p> p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 11.0px Times} span.s1 {font: 7.0px Times} span.s2 {font: 11.0px Helvetica} <p>IsoLG decreased HDL-mediated 3H-cholesterol</p> <p>efflux from macrophages via ABCA1, which</p> <p>corresponded to a decrease in HDL-apoA-I exchange</p> <p>from 47.4% to only 24.8%. This suggests</p> <p>that IsoLG inhibits apoA-I from disassociating</p> <p>from HDL to interact with ABCA1. Addition of</p> <p>0.3 eq IsoLG ablated HDL’s ability to inhibit</p> <p>LPS-stimulated cytokine expression by macrophages,</p> <p>and increased IL-1β expression by 3.5-</p> <p>fold. The structural-functional effects were partially</p> <p>rescued with PPM scavenging.</p> p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 11.0px Times} span.s1 {font: 7.0px Times} span.s2 {font: 11.0px Helvetica} <p>generating a subpopulation of 16-23 nm. 1 eq.</p> <p>IsoLG decreased HDL-mediated 3H-cholesterol</p> <p>efflux from macrophages via ABCA1, which</p> <p>corresponded to a decrease in HDL-apoA-I exchange</p> <p>from 47.4% to only 24.8%. This suggests</p> <p>that IsoLG inhibits apoA-I from disassociating</p> <p>from HDL to interact with ABCA1. Addition of</p> <p>0.3 eq IsoLG ablated HDL’s ability to inhibit</p> <p>LPS-stimulated cytokine expression by macrophages,</p> <p>and increased IL-1β expression by 3.5-</p> <p>fold. The structural-functional effects were partially</p> <p>rescued with PPM scavenging.</p>