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

An-Sheng Lee1234, Wei-Yu Chen4, Hua-Chen Chan47, Jing-Fang Hsu4, Ming-Yi Shen34, Chia-Ming Chang4, Henry Bair5, Ming-Jai Su6, Kuan-Cheng Chang23* and Chu-Huang Chen34789*

Author Affiliations

1 Department of Medicine, Mackay Medical College, New Taipei, Taiwan

2 Division of Cardiology, China Medical University Hospital, Taichung City, Taiwan

3 Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan

4 L5 Research Center, China Medical University Hospital, Taichung, Taiwan

5 George R. Brown School of Engineering, Rice University, Houston, Texas, USA

6 Graduate Institute of Pharmacology, National Taiwan University, Taipei, Taiwan

7 Center for Lipid Biosciences and Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

8 Vascular and Medicinal Research, Texas Heart Institute, 6770 Bertner Avenue, MC 2-255, Houston, TX 77030, USA

9 Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

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Cardiovascular Diabetology 2014, 13:64  doi:10.1186/1475-2840-13-64

Published: 25 March 2014



Increased 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.


L5 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).


L5 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.


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

Electronegative low-density lipoprotein; Metabolic syndrome; Cardiovascular disease; Aortic senescence; 17β-estradiol; Genistein