Gender disparity in LDL-induced cardiovascular damage and the protective role of estrogens against electronegative LDLReport as inadecuate

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Cardiovascular Diabetology

, 13:64

First Online: 25 March 2014Received: 10 February 2014Accepted: 28 February 2014


BackgroundIncreased levels of the most electronegative type of LDL, L5, have been observed in the plasma of patients with metabolic syndrome MetS and ST-segment elevation myocardial infarction and can induce endothelial dysfunction. Because men have a higher predisposition to developing coronary artery disease than do premenopausal women, we hypothesized that LDL electronegativity is increased in men and promotes endothelial damage.

MethodsL5 levels were compared between middle-aged men and age-matched, premenopausal women with or without MetS. We further studied the effects of gender-influenced LDL electronegativity on aortic cellular senescence and DNA damage in leptin receptor–deficient db-db mice by using senescence-associated–β-galactosidase and γH2AX staining, respectively. We also studied the protective effects of 17β-estradiol and genistein against electronegative LDL–induced senescence in cultured bovine aortic endothelial cells BAECs.

ResultsL5 levels were higher in MetS patients than in healthy subjects P < 0.001, particularly in men P = 0.001. LDL isolated from male db-db mice was more electronegative than that from male or female wild-type mice. In addition, LDL from male db-db mice contained abundantly more apolipoprotein CIII and induced more BAEC senescence than did female db-db or wild-type LDL. In the aortas of db-db mice but not wild-type mice, we observed cellular senescence and DNA damage, and the effect was more significant in male than in female db-db mice. Pretreatment with 17β-estradiol or genistein inhibited BAEC senescence induced by male or female db-db LDL and downregulated the expression of lectin-like oxidized LDL receptor-1 and tumor necrosis factor-alpha protein.

ConclusionThe gender dichotomy of LDL-induced cardiovascular damage may underlie the increased propensity to coronary artery disease in men.

KeywordsElectronegative low-density lipoprotein Metabolic syndrome Cardiovascular disease Aortic senescence 17β-estradiol Genistein AbbreviationsMetSMetabolic syndrome

CADCoronary artery disease

HDL-CHigh-density lipoprotein cholesterol

LDL-Clow-density lipoprotein cholesterol

ApoCIIIApolipoprotein CIII

db-dbHomozygous leptin receptor deficient


Anti-γH2AXAnti–phospho-histone H2AX

BAECBovine aortic endothelial cell

LOX-1Lectin-like oxidized LDL receptor-1

TNF-αTumor necrosis factor-α


Electronic supplementary materialThe online version of this article doi:10.1186-1475-2840-13-64 contains supplementary material, which is available to authorized users.

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Author: An-Sheng Lee - Wei-Yu Chen - Hua-Chen Chan - Jing-Fang Hsu - Ming-Yi Shen - Chia-Ming Chang - Henry Bair - Ming-Jai Su - K


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