Abstract
Aim:
This study was conducted to demonstrate the anti-atherosclerotic effect of dehydroepiandrosterone (DHEA) and to investigate its possible mechanisms and whether this effect is related to its conversion to estrogen.
Methods:
Forty male New Zealand White rabbits aged 3 months were divided into 5 groups (n=8 per group) and fed different diets for 10 weeks. Serum lipid levels, the area of atherosclerotic lesions and the mRNA levels of monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) in aortic lesions were measured. Then cultured vascular smooth muscle cells (VSMCs) stimulated by oxidized low density lipoprotein-cholesterol (ox-LDL) were treated by DHEA. The gene and protein expression levels of MCP-1 and VCAM-1 in VSMCs was detected. The plasmid with or without the gene of cytochrome P450 aromatase (CYP19) was transient transfected into cultured VSMCs respectively. Twenty hours later, the cells were stimulated with ox-LDL and DHEA.
Results:
DHEA could obviously decrease the area of atherosclerotic lesions and the expressions of MCP-1 and VCAM-1 in aortic lesions. But all-trans retinoic acid (atRA) which was reported would limit restenosis after balloon angioplasty had no visible synergistic effect with DHEA. DHEA could also reduce ox-LDL-induced MCP-1 and VCAM-1 expression in untransfected or transfected VSMCs.
Conclusion:
The anti-atherosclerotic effect of DHEA had nothing to do with the catalysis of cytochrome P450 aromatase (CYP19), or was not related to its conversion to estrogen.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Parker CR . Dehydroepiandrosterone and dehydroepiandrosterone sulfate production in the human adrenal during development and aging. Steroids 1999; 64: 640–7.
Zdrojewicz Z, Ciszko B . Dehydroepiandrosterone (DHEA)-structure, clinical importance and the role in human body. Postepy Hig Med Dosw 2001; 55: 835–54.
Williams JR . The effects of dehydroepiandrosterone on carcinogenesis, obesity, the immune system, and aging. Lipids 2000; 35: 325–31.
PorŠovÁ-dutoit I, ŠulcovÁ J, StÁrka L . Do DHEA/DHEAS play a protective role in coronary heart disease? Physiol Res 2000; 49 (Suppl 1): S43–S56.
Fredrick CWW, Arnold VE . Androgens and coronary artery disease. Endocrine Rev 2003; 24: 183–217.
Dimitrakakis C, Zhou J, Bondy CA . Androgens and mammary growth and neoplasia. Fertil Steril 2002; 77: S26–S33.
Notelovitz M . Androgen effects on bone and muscle. Fertil Steril 2002; 77: S34–S41.
Hayashi T, Muto E, Kano H, Asai Y, Thakur NK, et al. Dehydroepiandrosterone retards atherosclerosis formation through its conversion to estrogen: the possible role of nitric oxide. Arterioscler Thromb Vasc Biol 2000; 20: 782–92.
Yoneyama A, Kamiya Y, Kawaguchi M, Fujinami T . Effects of dehydroepiandrosterone on proliferation of human aortic muscle cells. Life Sci 1997; 60: 833–8.
Ross R . Cell biology of atherosclerosis. Annu Rev Physiol 1995; 57: 791–804.
Takahashi M, Ikeda U, Masuyama J, Kitagawa S, Kasahara T, Saito M, et al. Involvement of adhesion molecules in human monocyte adhesion to and transmigration through endothelial cells in vitro. Atherosclerosis 1994; 108: 73–81.
Valente AJ, Rozek MM, Sprague EA, Schwartz CJ . Mechanisms in intimal monocyte-macrophage recruitment: a special role for monocyte chemotactic protein-1. Circulation 1992; 86 (Suppl III): III-20–III-25.
Kuijpers TW, Harlan JM . Monocyte-endothelial interactions: insights and questions. J Lab Clin Med 1993; 122: 641–51.
Iivama K, Hajra L, Iiyama M, Li H, DiChiara M, Medoff BD, et al. Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res 1999; 85: 199–207.
Walker LN, Reidy MA, Bowyer DE . Morphology and cell kinetics of fatty streak lesion formation in the hypercholesterolemic rabbit. Am J Pathol 1986; 125: 450–9.
Parhami F, Fang ZT, Fogelman AM, Andalibi A, Territo MC, Berliner JA . Minimally modified low density lipoprotein-induced inflammatory responses in endothelial cells are mediated by cyclic adenosine monophosphate. J Clin Invest 1993; 92: 471–8.
Nelken NA, Coughlin SR, Gordon D, Wilcox JN . Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest 1991; 88: 1121–7.
Freshney RI . Culture of Animal Cells: A Manual of Basic Technique. New York: Alan R. Liss, Inc; 1987.
Rao MS, Ide RE, Subbarao V, Reddy AJ . Dehydroepiandrosterone induced peroxisome proliferation in the rat: evaluation of sex differences. Proc Soc Exp Biol Med 1994; 20: 186–90.
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL . Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989; 320: 915–24.
Brown AJ . Atherosclerosis: Cell biology and lipoproteins. Curr Opin Lipidol 2000; 11: 667–9.
Schwartz CJ, Valente AJ, Sprague EA, Kelley JL, Nerem RM . The pathogenesis of atherosclerosis: an overview. Clin Cardiol 1991; 14(2 Suppl 1): 11–6.
Barret-Connor E, Goodman-Gruen D . The epidemiology of DHEAS and cardiovascular disease. Ann NY Acad Sci 1995; 774: 259–70.
López-Marure R, Huesca-Gómez C, Ibarra-Sánchez Mde J, Zentella A, Pérez-Méndez O . Dehydroepiandrosterone delays LDL oxidation in vitro and attenuates several oxLDL-induced inflammatory responses in endothelial cells. Inflamm Allergy Drug Targets 2007; 6: 174–82.
Vatalas IA, Diony-Asteriou A . Adrenal C19 steroids and lipoprotein levels in healthy men. Nutr Metab Cardiovasc Dis 2001; 1: 388–93.
Moriyama Y, Yasue H, Yoshimura M, Mizuno Y, Nishiyama K, Tsunoda R, et al. The plasma levels of dehydroepiandrosterone sulfate are decreased in patients with chronic heart failure in proportion to the severity. J Clin Endocrinol Metab 2000; 85: 1834–40.
Silvestri A, Gambacciani M, Vitale C, Monteleone P, Ciaponi M, Fini M, et al. Different effect of hormone replacement therapy, DHEAS and tibolone on endothelial function in postmenopausal women with increased cardiovascular risk. Maturitas 2005; 50: 305–11.
Callies F, Fassnacht M, van Vlijmen JC, Koehler I, Huebler D, Seibel MJ, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency: effects on body composition, serum leptin, bone turnover, and exercise capacity. J Clin Endocrinol Metab 2001; 86: 1968–72.
Hayashi T, Esaki T, Muto E, Kano H, Asai Y, Thakur NK, et al. Dehydroepiandrosterone retards atherosclerosis formation through its conversion to estrogen: The possible role of nitric oxide. Arterioscler Thromb Vasc Biol 2000; 20: 782–92.
Bouraima H, Hanoux V, Mittre H . Expression of the rabbit cytochrome P450 aromatase encoding gene uses alternative tissue-specific promoters. Eur J Biochem 2001; 268: 4506–12.
Shozu M, Zhao Y, Bulun SE, Simpson ER . Multiple splicing events involved in regulation of human aromatase expression by a novel promoter, I.6. Endocrinology 1998; 139: 1610–7.
Chen J, He B, Zheng D, Zhang S, Liu J, Zhu S . All-trans retinoic acid reduces intimal thickening after balloon angioplasty in atherosclerotic rabbits. Chin Med J (Engl) 1999; 112: 121–3.
Maiti S, Chen X, Chen G . All-trans retinoic acid induction of sulfotransferases. Basic Clin Pharmacol Toxicol 2005; 96: 44–53.
Liu D, Dillon JS . Dehydroepiandrosterone activates endothelial cell nitric-oxide synthase by a specific plasma 386 seminars in reproductive medicine/volume 22, number 4 2004 membrane receptor coupled to Galpha(i2,3). J Biol Chem 2002; 277: 21 379–88.
Furutama D, Fukui R, Amakawa M, Ohsawa N . Inhibition of migration and proliferation of vascular smooth muscle cells by dehydroepiandrosterone sulfate. Biochim Biophys Acta 1998; 1406: 107–14.
Simoncini T, Mannella P, Fornari L, Varone G, Caruso A, Genazzani AR . Dehydroepiandrosterone modulates endothelial nitric oxide synthesis via direct genomic and nongenomic mechanisms. Endocrinology 2003; 144: 3449–55.
Williams MR, Ling S, Dawood T, Hashimura K, Dai A, Li H, et al. Dehydroepiandrosterone inhibits human vascular smooth muscle cell proliferation independent of ARs and ERs. J Clin Endocrinol Metab 2002; 87: 176–81.
Zapata E, Ventura JL, De la Cruz K, Rodriguez E, Damián P, Massó F, et al. Dehydroepiandrosterone inhibits the proliferation of human umbilical vein endothelial cells by enhancing the expression of p53 and p21, restricting the phosphorylation of retinoblastoma protein, and is androgen- and estrogenreceptor independent. FEBS J 2005; 272: 1343–53.
Daynes RA, Araneo BA, Ershler WB, Maloney C, Li GZ, Ryu SY . Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative. J Immunol 1993; 150: 5219–30.
Spencer NF, Norton SD, Harrison LL, Li GZ, Daynes RA . Dysregulation of IL-10 production with aging: possible linkage to the age-associated decline in DHEA and its sulfated derivative. Exp Gerontol 1996; 31: 393–408.
Gutiérrez G, Zapata E, Montiel A, Reyes E, Montaño LF, et al. Dehydroepiandrosterone inhibits the TNF-alpha-induced inflammatory response in human umbilical vein endothelial cells. Atherosclerosis 2007; 190: 90–9.
Acknowledgements
Project supported by grants from the National Natural Science Foundation of China (No 30300135 and 30570725), Natural Science Foundation of Hubei Province (No 2005ABA166).
We thank Alan J CONLEY for providing plasmid and Shou-hua YANG for expert technical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cheng, Hh., Hu, Xj. & Ruan, Qr. Dehydroepiandrosterone anti-atherogenesis effect is not via its conversion to estrogen. Acta Pharmacol Sin 30, 42–53 (2009). https://doi.org/10.1038/aps.2008.2
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2008.2
Keywords
This article is cited by
-
Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay
Acta Pharmacologica Sinica (2014)
-
DHEA supplementation in Menopause
Current Obstetrics and Gynecology Reports (2014)
