Abstract
The effect of estrogen and progesterone replacement therapy on the initiating events in atherogenesis was studied in surgically postmenopausal cynomolgus monkeys. Monkeys were ovariectomized and divided randomly into two groups, one receiving 17 beta-estradiol and cyclic progesterone treatment (n = 9) and ovariectomized controls receiving no hormone replacement therapy (n = 8). The monkeys were fed a moderately atherogenic diet for 18 wk to accelerate the early pathogenic processes but not to be of sufficient duration to produce grossly visible atherosclerotic lesions. Sex hormone replacement therapy decreased the accumulation of LDL and products of LDL degradation in the coronary arteries by greater than 70% while having no significant effect on plasma lipid, lipoprotein, or apoprotein concentrations. Arterial intimal lesions were small with no difference between groups. The reduction in arterial LDL metabolism occurred very early in the pathogenesis of atherosclerosis and was independent of indices of endothelial cell injury, such as enhanced endothelial cell turnover or leukocyte adhesion to the endothelium. Results of this study suggest that one mechanism by which sex hormone treatment inhibits the initiation of atherosclerosis is a direct effect at the level of the arterial wall by suppressing the uptake and/or degradation of LDL.
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- Adams M. R., Kaplan J. R., Clarkson T. B., Koritnik D. R. Ovariectomy, social status, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis. 1985 Mar-Apr;5(2):192–200. doi: 10.1161/01.atv.5.2.192. [DOI] [PubMed] [Google Scholar]
- Adams M. R., Kaplan J. R., Koritnik D. R. Psychosocial influences on ovarian endocrine and ovulatory function in Macaca fascicularis. Physiol Behav. 1985 Dec;35(6):935–940. doi: 10.1016/0031-9384(85)90262-8. [DOI] [PubMed] [Google Scholar]
- Adams M. R., Kaplan J. R., Manuck S. B., Koritnik D. R., Parks J. S., Wolfe M. S., Clarkson T. B. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone. Arteriosclerosis. 1990 Nov-Dec;10(6):1051–1057. doi: 10.1161/01.atv.10.6.1051. [DOI] [PubMed] [Google Scholar]
- Adams M. R., Kaplan J. R., Manuck S. B., Uberseder B., Larkin K. T. Persistent sympathetic nervous system arousal associated with tethering in cynomolgus macaques. Lab Anim Sci. 1988 Jun;38(3):279–281. [PubMed] [Google Scholar]
- Allain C. C., Poon L. S., Chan C. S., Richmond W., Fu P. C. Enzymatic determination of total serum cholesterol. Clin Chem. 1974 Apr;20(4):470–475. [PubMed] [Google Scholar]
- BLIGH E. G., DYER W. J. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959 Aug;37(8):911–917. doi: 10.1139/o59-099. [DOI] [PubMed] [Google Scholar]
- Basdevant A., De Lignieres B., Guy-Grand B. Differential lipemic and hormonal responses to oral and parenteral 17 beta-estradiol in postmenopausal women. Am J Obstet Gynecol. 1983 Sep 1;147(1):77–81. doi: 10.1016/0002-9378(83)90088-1. [DOI] [PubMed] [Google Scholar]
- Bilheimer D. W., Eisenberg S., Levy R. I. The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations. Biochim Biophys Acta. 1972 Feb 21;260(2):212–221. doi: 10.1016/0005-2760(72)90034-3. [DOI] [PubMed] [Google Scholar]
- Bush T. L., Barrett-Connor E., Cowan L. D., Criqui M. H., Wallace R. B., Suchindran C. M., Tyroler H. A., Rifkind B. M. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation. 1987 Jun;75(6):1102–1109. doi: 10.1161/01.cir.75.6.1102. [DOI] [PubMed] [Google Scholar]
- Carew T. E., Pittman R. C., Marchand E. R., Steinberg D. Measurement in vivo of irreversible degradation of low density lipoprotein in the rabbit aorta. Predominance of intimal degradation. Arteriosclerosis. 1984 May-Jun;4(3):214–224. doi: 10.1161/01.atv.4.3.214. [DOI] [PubMed] [Google Scholar]
- Carew T. E., Schwenke D. C., Steinberg D. Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7725–7729. doi: 10.1073/pnas.84.21.7725. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carroll R. M., Rudel L. L. Lipoprotein separation and low density lipoprotein molecular weight determination using high performance gel-filtration chromatography. J Lipid Res. 1983 Feb;24(2):200–207. [PubMed] [Google Scholar]
- Chao Y. S., Windler E. E., Chen G. C., Havel R. J. Hepatic catabolism of rat and human lipoproteins in rats treated with 17 alpha-ethinyl estradiol. J Biol Chem. 1979 Nov 25;254(22):11360–11366. [PubMed] [Google Scholar]
- Clarkson T. B., Lombardi D. M., Alexander N. J., Lewis J. C. Diet and vasectomy: effects on atherogenesis in cynomolgus macaques. Exp Mol Pathol. 1986 Feb;44(1):29–49. doi: 10.1016/0014-4800(86)90031-6. [DOI] [PubMed] [Google Scholar]
- Cronin M. J., Koritnik D. R. Dopamine receptors of the monkey anterior pituitary in various endocrine states. Endocrinology. 1983 Feb;112(2):618–623. doi: 10.1210/endo-112-2-618. [DOI] [PubMed] [Google Scholar]
- Fossati P., Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem. 1982 Oct;28(10):2077–2080. [PubMed] [Google Scholar]
- Fåhraeus L., Wallentin L. High density lipoprotein subfractions during oral and cutaneous administration of 17 beta-estradiol to menopausal women. J Clin Endocrinol Metab. 1983 Apr;56(4):797–801. doi: 10.1210/jcem-56-4-797. [DOI] [PubMed] [Google Scholar]
- Gidez L. I., Miller G. J., Burstein M., Slagle S., Eder H. A. Separation and quantitation of subclasses of human plasma high density lipoproteins by a simple precipitation procedure. J Lipid Res. 1982 Nov;23(8):1206–1223. [PubMed] [Google Scholar]
- Godsland I. F., Wynn V., Crook D., Miller N. E. Sex, plasma lipoproteins, and atherosclerosis: prevailing assumptions and outstanding questions. Am Heart J. 1987 Dec;114(6):1467–1503. doi: 10.1016/0002-8703(87)90552-7. [DOI] [PubMed] [Google Scholar]
- Goldstein J. L., Brown M. S. The low-density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem. 1977;46:897–930. doi: 10.1146/annurev.bi.46.070177.004341. [DOI] [PubMed] [Google Scholar]
- Hough J. L., Zilversmit D. B. Effect of 17 beta estradiol on aortic cholesterol content and metabolism in cholesterol-fed rabbits. Arteriosclerosis. 1986 Jan-Feb;6(1):57–63. doi: 10.1161/01.atv.6.1.57. [DOI] [PubMed] [Google Scholar]
- Huber L. A., Scheffler E., Poll T., Ziegler R., Dresel H. A. 17 beta-estradiol inhibits LDL oxidation and cholesteryl ester formation in cultured macrophages. Free Radic Res Commun. 1990;8(3):167–173. doi: 10.3109/10715769009087990. [DOI] [PubMed] [Google Scholar]
- Jerome W. G., Lewis J. C. Early atherogenesis in White Carneau pigeons. I. Leukocyte margination and endothelial alterations at the celiac bifurcation. Am J Pathol. 1984 Jul;116(1):56–68. [PMC free article] [PubMed] [Google Scholar]
- Kaplan J. R., Adams M. R., Clarkson T. B., Koritnik D. R. Psychosocial influences on female 'protection' among cynomolgus macaques. Atherosclerosis. 1984 Dec;53(3):283–295. doi: 10.1016/0021-9150(84)90129-1. [DOI] [PubMed] [Google Scholar]
- Koritnik D. L., Rudel L. L. Measurement of apolipoprotein A-I concentration in nonhuman primate serum by enzyme-linked immunosorbent assay (ELISA). J Lipid Res. 1983 Dec;24(12):1639–1645. [PubMed] [Google Scholar]
- Kovanen P. T., Brown M. S., Goldstein J. L. Increased binding of low density lipoprotein to liver membranes from rats treated with 17 alpha-ethinyl estradiol. J Biol Chem. 1979 Nov 25;254(22):11367–11373. [PubMed] [Google Scholar]
- LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
- MacDonald G. J. Reproductive patterns of three species of macaques. Fertil Steril. 1971 Jun;22(6):373–377. [PubMed] [Google Scholar]
- Parks J. S., Kaduck-Sawyer J., Bullock B. C., Rudel L. L. Effect of dietary fish oil on coronary artery and aortic atherosclerosis in African green monkeys. Arteriosclerosis. 1990 Nov-Dec;10(6):1102–1112. doi: 10.1161/01.atv.10.6.1102. [DOI] [PubMed] [Google Scholar]
- Parks J. S., Pelkey S. J., Babiak J., Clarkson T. B. Contraceptive steroid effects on lipids and lipoproteins in cynomolgus monkeys. Arteriosclerosis. 1989 Mar-Apr;9(2):261–268. doi: 10.1161/01.atv.9.2.261. [DOI] [PubMed] [Google Scholar]
- Pittman R. C., Carew T. E., Glass C. K., Green S. R., Taylor C. A., Jr, Attie A. D. A radioiodinated, intracellularly trapped ligand for determining the sites of plasma protein degradation in vivo. Biochem J. 1983 Jun 15;212(3):791–800. doi: 10.1042/bj2120791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rudel L. L., Bond M. G., Bullock B. C. LDL heterogeneity and atherosclerosis in nonhuman primates. Ann N Y Acad Sci. 1985;454:248–253. doi: 10.1111/j.1749-6632.1985.tb11864.x. [DOI] [PubMed] [Google Scholar]
- Rudel L. L., Lee J. A., Morris M. D., Felts J. M. Characterization of plasma lipoproteins separated and purified by agarose-column chromatography. Biochem J. 1974 Apr;139(1):89–95. doi: 10.1042/bj1390089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schwenke D. C., Carew T. E. Initiation of atherosclerotic lesions in cholesterol-fed rabbits. I. Focal increases in arterial LDL concentration precede development of fatty streak lesions. Arteriosclerosis. 1989 Nov-Dec;9(6):895–907. doi: 10.1161/01.atv.9.6.895. [DOI] [PubMed] [Google Scholar]
- Schwenke D. C., Carew T. E. Quantification in vivo of increased LDL content and rate of LDL degradation in normal rabbit aorta occurring at sites susceptible to early atherosclerotic lesions. Circ Res. 1988 Apr;62(4):699–710. doi: 10.1161/01.res.62.4.699. [DOI] [PubMed] [Google Scholar]
- Schwenke D. C., Zilversmit D. B. The arterial barrier to lipoprotein influx in the hypercholesterolemic rabbit. 2. Long-term studies in deendothelialized and reendothelialized aortas. Atherosclerosis. 1989 Jun;77(2-3):105–115. doi: 10.1016/0021-9150(89)90072-5. [DOI] [PubMed] [Google Scholar]
- Sorci-Thomas M., Wilson M. D., Johnson F. L., Williams D. L., Rudel L. L. Studies on the expression of genes encoding apolipoproteins B100 and B48 and the low density lipoprotein receptor in nonhuman primates. Comparison of dietary fat and cholesterol. J Biol Chem. 1989 May 25;264(15):9039–9045. [PubMed] [Google Scholar]
- St Clair R. W., Leight M. A. Cholesterol efflux from cells enriched with cholesteryl esters by incubation with hypercholesterolemic monkey low density lipoprotein. J Lipid Res. 1983 Feb;24(2):183–191. [PubMed] [Google Scholar]
- St Clair R. W., Mitschelen J. J., Leight M. Metabolism by cells in culture of low-density lipoproteins of abnormal composition from non-human primates with diet-induced hypercholesterolemia. Biochim Biophys Acta. 1980 Apr 18;618(1):63–79. doi: 10.1016/0005-2760(80)90054-5. [DOI] [PubMed] [Google Scholar]
- Veldhuis J. D., Gwynne J. T. Estrogen regulates low density lipoprotein metabolism by cultured swine granulosa cells. Endocrinology. 1985 Oct;117(4):1321–1327. doi: 10.1210/endo-117-4-1321. [DOI] [PubMed] [Google Scholar]
- Windler E. E., Kovanen P. T., Chao Y. S., Brown M. S., Havel R. J., Goldstein J. L. The estradiol-stimulated lipoprotein receptor of rat liver. A binding site that membrane mediates the uptake of rat lipoproteins containing apoproteins B and E. J Biol Chem. 1980 Nov 10;255(21):10464–10471. [PubMed] [Google Scholar]
- Yedgar S., Carew T. E., Pittman R. C., Beltz W. F., Steinberg D. Tissue sites of catabolism of albumin in rabbits. Am J Physiol. 1983 Jan;244(1):E101–E107. doi: 10.1152/ajpendo.1983.244.1.E101. [DOI] [PubMed] [Google Scholar]