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REGULATION OF BIGLYCAN EXPRESSION BY SEX HORMONES UNIFIES THE CLINICAL TENETS OF ATHEROSCLEROSIS
Submit responseDear Sir:
After decades of controversies that shed more heat than light over the conflicting effects of endogenous and exogenous sex hormones on cardiovascular disease (CVD), two large studies have finally advanced our current thinking. The first is the Women¡¦s Health Initiative (WHI) Study that showed an overall greater risk-to-benefit ratio of exogenous estrogen in postmenopausal females (1). The second is this seminary Framingham study by Arnlov J et al. (2) that showed the reduced CVD event rates in older men with higher estrogen levels, thereby suggesting a vasculoprotective effect of endogenous estrogens. The authors are to be congratulated for the well conceived study design adequately powered to address this question.
In contrast, no vasculoprotective effect of testosterone or dehydroepiandrosterone sulfate (DHEA-S) was found, and that endogenous estrogen does not confer similar protection in younger men. Whenever large scale, prospective epidemiological studies have successfully ¡§filtered out the signal from the noise¡¨ and borne striking or counterintuitive data, real biological phenomena probably exist that merit further translational research. In this instance, Arnlov et al. have highlighted plausible mechanisms for the estrogens-CVD risk linkage including traditional (blood pressure, lipids, glycemia) and non-traditional risk factors (homocysteine, hemostatic factors, inflammation, endothelial function). However, it remains mysterious how estrogen operates on such factors at the molecular level. Notably, they quoted from literature that genetic variation in estrogen receptor-ƒÑ has been associated with higher CVD events, and that androgen and estrogen receptor expression in coronary arteries has been reported to influence coronary atherosclerosis in men.
To lend greater scientific credence to their findings, we should draw our attention to the increasing role of extracellular matrix proteoglycans called biglycan, in atherogenesis. Biglycan tends to bind low density lipoprotein (LDL) in the subendothelium and is proinflammatory (3). In addition, biglycan modulate structural integrity and biophysical properties of the vessel wall by decreasing arterial compliance while increasing its stiffness. DNA microarray technology has unraveled reduction of biglycan expression by estradiol and phytoestrogens (4), though regulation of biglycan expression by other exogenous estrogens is still unknown. Testosterone, however, upregulate vascular proteoglycan expression, and increases their binding to LDL (5). These compelling novel molecular findings on biglycan-sex hormone-lipid interactions seem to unify most of the macroscopic tenets of atherosclerosis and agree well with clinical observations.
Yours sincerely,
Melvin Khee-Shing Leow, MD, FACE, FACP
References
1. Roussouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women¡¦s Health Initiative randomized controlled trial. JAMA 2002; 288: 321-333.
2. Arnlov J, Pencina MJ, Amin S, et al. Endogenous sex hormones and cardiovascular disease incidence in men. Ann Intern Med 2006; 145: 176- 184.
3. Figueroa JE, Vijayagopal P. Angiotensin II stimulates synthesis of vascular smooth muscle cell proteoglycans with enhanced low density lipoprotein binding properties. Atherosclerosis 2002; 162: 261-268.
4. Rodrigo MC, Martin DS, Eyster KM. Estrogen decreases biglycan mRNA expression in resistance blood vessels. Am J Physiol Regul Integr Comp Physiol 2003; 285: R754-761.
5. Hashimura K, Sudhir K, Nigro J, et al. Androgens stimulate human vascular smooth muscle proteoglycan biosynthesis and increase lipoprotein binding. Endocrinology 2005; 146: 2085-90.
Conflict of Interest:
None declared