Modification by acrolein, a component of tobacco smoke and age-related oxidative stress, mediates functional impairment of human apolipoprotein E.
Oxidative damage to proteins such as apolipoprotein B-100 increases the atherogenicity of low-density lipoproteins (LDL). However, little is known about the potential oxidative damage to apolipoprotein E (apoE), an exchangeable antiatherogenic apolipoprotein. ApoE plays an integral role in lipoprotein metabolism by regulating the plasma cholesterol and triglyceride levels. Hepatic uptake of lipoproteins is facilitated by apoE's ability to bind with cell surface heparan sulfate proteoglycans and to lipoprotein receptors via basic residues in its 22 kDa N-terminal domain (NT). We investigated the effect of acrolein, an aldehydic product of endogenous lipid peroxidation and a tobacco smoke component, on the conformation and function of recombinant human apoE3-NT. Acrolein caused oxidative modification of apoE3-NT as detected by Western blot with acrolein-lysine-specific antibodies, and tertiary conformational alterations. Acrolein modification impairs the ability of apoE3-NT to interact with heparin and the LDL receptor. Furthermore, acrolein-modified apoE3-NT displayed a 5-fold decrease in its ability to interact with lipid surfaces. Our data indicate that acrolein disrupts the functional integrity of apoE3, which likely interferes with its role in regulating plasma cholesterol homeostasis. These observations have implications regarding the role of apoE in the pathogenesis of smoking- and oxidative stress-mediated cardiovascular and cerebrovascular diseases.
Tamamizu-Kato
Shiori
S
Center for the Prevention of Obesity, Cardiovascular Disease and Diabetes, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, California 94609, USA.
Wong
Jason Yiu
JY
Jairam
Vikram
V
Uchida
Koji
K
Raussens
Vincent
V
Kato
Hiroyuki
H
Ruysschaert
Jean-Marie
JM
Narayanaswami
Vasanthy
V
D000171:Acrolein / Q000494:pharmacology*; D000375:Aging; D053318:Apolipoprotein E3 / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress; D010743:Phospholipids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000378:metabolism; D012907:Smoking
D053318:Apolipoprotein E3; D010743:Phospholipids; D011973:Receptors, LDL; D000171:Acrolein; D006493:Heparin