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Open Access Highly Accessed Original investigation

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

Abstract

Background

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.

Methods

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).

Results

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.

Conclusion

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

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