| Summary: | The most electronegative constituents of human plasma LDL (i.e., L5) and VLDL (i.e., V5) are highly atherogenic. We determined whether the combined electronegativity of L5 and V5 (i.e., L5 + V5) plays a role in coronary heart disease (CHD). In 33 asymptomatic individuals (ages 32−64), 10-year hard CHD risk correlated with age (r = 0.42, <i>p</i> = 0.01). However, in age-adjusted analyses, 10-year hard CHD risk correlated with L5 + V5 plasma concentration (r = 0.43, <i>p</i> = 0.01) but not age (<i>p</i> = 0.74). L5 + V5 plasma concentration was significantly greater in the group with high CHD risk (39.4 ± 22.0 mg/dL; <i>n</i> = 17) than in the group with low CHD risk (16.9 ± 14.8 mg/dL; <i>n</i> = 16; <i>p</i> = 0.01). In cultured human aortic endothelial cells, L5 + V5 treatment induced significantly more senescence-associated−β-Gal activity than did equal concentrations of L1 + V1 (<i>n</i> = 4, <i>p</i> < 0.001). To evaluate the in vivo relevance of these findings, we fed ApoE<sup>−/−</sup> and wild-type mice with a high-fat diet and found that plasma LDL, VLDL, and LDL + VLDL from ApoE<sup>−/−</sup> mice exhibited significantly greater electrophoretic mobility than did wild-type counterparts (<i>n</i> = 6, <i>p</i> < 0.01). The increased electronegativity of LDL and VLDL in ApoE<sup>−/−</sup> mice was accompanied by increased aortic lipid accumulation and cellular senescence (<i>n</i> = 6, <i>p</i> < 0.05). Clinical trials are warranted to test the predictive value of L5 + V5 concentration in patients with CHD.
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