Abstract
The aim was to investigate the atherogenic potential of lipoprotein(a) (Lp(a)) and to further our understanding of the atherogenic process by measuring rates of transfer into the intima-inner media (i.e., intimal clearance) and rates of loss from the intima-inner media (i.e., fractional loss) of Lp(a) and LDL using cholesterol-fed rabbits with nonlesioned (n = 13) or atherosclerotic aortas (n = 12). In each rabbit, 131I-Lp(a) (or 131I-LDL) was injected intravenously 26 h before and 125I-Lp(a) (or 125I-LDL) 3 h before the aorta was removed and divided into six consecutive segments of similar size. The intimal clearance of Lp(a) and LDL was similar and markedly increased in atherosclerotic compared with nonlesioned aortas (ANOVA, effect of atherosclerosis: P < 0.0001). Fractional losses of labeled Lp(a) and labeled LDL in atherosclerotic aorta were on average 25 and 43%, respectively, of that in nonlesioned aortas (ANOVA, effect of atherosclerosis: P < 0.0001). Fractional loss of Lp(a) was 73% of that of LDL (ANOVA, effect of type of lipoprotein: P = 0.07). These data suggest that the development of atherosclerosis is associated with increased influx as well as decreased fractional loss of Lp(a) and LDL from the intima. Accordingly, Lp(a) may share with LDL the potential for causing atherosclerosis.
Full Text
The Full Text of this article is available as a PDF (216.7 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bihari-Varga M., Gruber E., Rotheneder M., Zechner R., Kostner G. M. Interaction of lipoprotein Lp(a) and low density lipoprotein with glycosaminoglycans from human aorta. Arteriosclerosis. 1988 Nov-Dec;8(6):851–857. doi: 10.1161/01.atv.8.6.851. [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]
- Bottalico L. A., Keesler G. A., Fless G. M., Tabas I. Cholesterol loading of macrophages leads to marked enhancement of native lipoprotein(a) and apoprotein(a) internalization and degradation. J Biol Chem. 1993 Apr 25;268(12):8569–8573. [PubMed] [Google Scholar]
- Cardoso L. E., Mourão P. A. Glycosaminoglycan fractions from human arteries presenting diverse susceptibilities to atherosclerosis have different binding affinities to plasma LDL. Arterioscler Thromb. 1994 Jan;14(1):115–124. doi: 10.1161/01.atv.14.1.115. [DOI] [PubMed] [Google Scholar]
- Chapman M. J. Comparative analysis of mammalian plasma lipoproteins. Methods Enzymol. 1986;128:70–143. doi: 10.1016/0076-6879(86)28063-5. [DOI] [PubMed] [Google Scholar]
- Cushing G. L., Gaubatz J. W., Nava M. L., Burdick B. J., Bocan T. M., Guyton J. R., Weilbaecher D., DeBakey M. E., Lawrie G. M., Morrisett J. D. Quantitation and localization of apolipoproteins [a] and B in coronary artery bypass vein grafts resected at re-operation. Arteriosclerosis. 1989 Sep-Oct;9(5):593–603. doi: 10.1161/01.atv.9.5.593. [DOI] [PubMed] [Google Scholar]
- FOLCH J., LEES M., SLOANE STANLEY G. H. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957 May;226(1):497–509. [PubMed] [Google Scholar]
- Fless G. M., Snyder M. L. Polymorphic forms of Lp(a) with different structural and functional properties: cold-induced self-association and binding to fibrin and lysine-Sepharose. Chem Phys Lipids. 1994 Jan;67-68:69–79. doi: 10.1016/0009-3084(94)90125-2. [DOI] [PubMed] [Google Scholar]
- Fless G. M., ZumMallen M. E., Scanu A. M. Isolation of apolipoprotein(a) from lipoprotein(a). J Lipid Res. 1985 Oct;26(10):1224–1229. [PubMed] [Google Scholar]
- Ghosh S., Armstrong M. L., Megan M. B., Cheng F. H. Arterial uptake indices of low density lipoproteins after fatty streak formation in Cynomolgus monkeys. Cardiovasc Res. 1987 Jan;21(1):14–20. doi: 10.1093/cvr/21.1.14. [DOI] [PubMed] [Google Scholar]
- Grainger D. J., Kirschenlohr H. L., Metcalfe J. C., Weissberg P. L., Wade D. P., Lawn R. M. Proliferation of human smooth muscle cells promoted by lipoprotein(a). Science. 1993 Jun 11;260(5114):1655–1658. doi: 10.1126/science.8503012. [DOI] [PubMed] [Google Scholar]
- Hansen B. F., Mortensen A., Hansen J. F., Ibsen P., Frandsen H., Nordestgaard B. G. Atherosclerosis in Watanabe heritable hyperlipidaemic rabbits. Evaluation by macroscopic, microscopic and biochemical methods and comparison of atherosclerosis variables. APMIS. 1994 Mar;102(3):177–190. [PubMed] [Google Scholar]
- Howard G. C., Pizzo S. V. Lipoprotein(a) and its role in atherothrombotic disease. Lab Invest. 1993 Oct;69(4):373–386. [PubMed] [Google Scholar]
- Jacobsson L. S., Persson K., Aberg G., Andersson R. G., Karlberg B. E., Olsson A. G. Antiatherosclerotic effects of the angiotensin-converting enzyme inhibitors captopril and fosinopril in hypercholesterolemic minipigs. J Cardiovasc Pharmacol. 1994 Oct;24(4):670–677. doi: 10.1097/00005344-199410000-00019. [DOI] [PubMed] [Google Scholar]
- Jennrich R. I., Schluchter M. D. Unbalanced repeated-measures models with structured covariance matrices. Biometrics. 1986 Dec;42(4):805–820. [PubMed] [Google Scholar]
- Jimi S., Sakata N., Matunaga A., Takebayashi S. Low density lipoproteins bind more to type I and III collagens by negative charge-dependent mechanisms than to type IV and V collagens. Atherosclerosis. 1994 May;107(1):109–116. doi: 10.1016/0021-9150(94)90146-5. [DOI] [PubMed] [Google Scholar]
- Knight B. L., Perombelon Y. F., Soutar A. K., Wade D. P., Seed M. Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects. Atherosclerosis. 1991 Apr;87(2-3):227–237. doi: 10.1016/0021-9150(91)90025-x. [DOI] [PubMed] [Google Scholar]
- Krempler F., Kostner G. M., Roscher A., Haslauer F., Bolzano K., Sandhofer F. Studies on the role of specific cell surface receptors in the removal of lipoprotein (a) in man. J Clin Invest. 1983 May;71(5):1431–1441. doi: 10.1172/JCI110896. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kreuzer J., Lloyd M. B., Bok D., Fless G. M., Scanu A. M., Lusis A. J., Haberland M. E. Lipoprotein (a) displays increased accumulation compared with low-density lipoprotein in the murine arterial wall. Chem Phys Lipids. 1994 Jan;67-68:175–190. doi: 10.1016/0009-3084(94)90137-6. [DOI] [PubMed] [Google Scholar]
- Lawn R. M., Wade D. P., Hammer R. E., Chiesa G., Verstuyft J. G., Rubin E. M. Atherogenesis in transgenic mice expressing human apolipoprotein(a) Nature. 1992 Dec 17;360(6405):670–672. doi: 10.1038/360670a0. [DOI] [PubMed] [Google Scholar]
- NESS A. T., PASTEWKA J. V., PEACOCK A. C. EVALUATION OF A RECENTLY REPORTED STABLE LIEBERMANN-BURCHARD REAGENT AND ITS USE FOR THE DIRECT DETERMINATION OF SERUM TOTAL CHOLESTEROL. Clin Chim Acta. 1964 Sep;10:229–237. doi: 10.1016/0009-8981(64)90140-8. [DOI] [PubMed] [Google Scholar]
- Nielsen L. B., Nordestgaard B. G., Stender S., Kjeldsen K. Aortic permeability to LDL as a predictor of aortic cholesterol accumulation in cholesterol-fed rabbits. Arterioscler Thromb. 1992 Dec;12(12):1402–1409. doi: 10.1161/01.atv.12.12.1402. [DOI] [PubMed] [Google Scholar]
- Nielsen L. B., Nordestgaard B. G., Stender S., Niendorf A., Kjeldsen K. Transfer of lipoprotein(a) and LDL into aortic intima in normal and in cholesterol-fed rabbits. Arterioscler Thromb Vasc Biol. 1995 Sep;15(9):1492–1502. doi: 10.1161/01.atv.15.9.1492. [DOI] [PubMed] [Google Scholar]
- Nielsen L. B., Stender S., Kjeldsen K., Nordestgaard B. G. Effect of angiotensin II and enalapril on transfer of low-density lipoprotein into aortic intima in rabbits. Circ Res. 1994 Jul;75(1):63–69. doi: 10.1161/01.res.75.1.63. [DOI] [PubMed] [Google Scholar]
- Nielsen L. B., Stender S., Kjeldsen K., Nordestgaard B. G. Specific accumulation of lipoprotein(a) in balloon-injured rabbit aorta in vivo. Circ Res. 1996 Apr;78(4):615–626. doi: 10.1161/01.res.78.4.615. [DOI] [PubMed] [Google Scholar]
- Niendorf A., Rath M., Wolf K., Peters S., Arps H., Beisiegel U., Dietel M. Morphological detection and quantification of lipoprotein(a) deposition in atheromatous lesions of human aorta and coronary arteries. Virchows Arch A Pathol Anat Histopathol. 1990;417(2):105–111. doi: 10.1007/BF02190527. [DOI] [PubMed] [Google Scholar]
- Nordestgaard B. G., Tybjaerg-Hansen A., Lewis B. Influx in vivo of low density, intermediate density, and very low density lipoproteins into aortic intimas of genetically hyperlipidemic rabbits. Roles of plasma concentrations, extent of aortic lesion, and lipoprotein particle size as determinants. Arterioscler Thromb. 1992 Jan;12(1):6–18. doi: 10.1161/01.atv.12.1.6. [DOI] [PubMed] [Google Scholar]
- Nordestgaard B. G., Wootton R., Lewis B. Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol. 1995 Apr;15(4):534–542. doi: 10.1161/01.atv.15.4.534. [DOI] [PubMed] [Google Scholar]
- Pyörälä K., De Backer G., Graham I., Poole-Wilson P., Wood D. Prevention of coronary heart disease in clinical practice. Recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. Eur Heart J. 1994 Oct;15(10):1300–1331. doi: 10.1093/oxfordjournals.eurheartj.a060388. [DOI] [PubMed] [Google Scholar]
- Rader D. J., Cain W., Ikewaki K., Talley G., Zech L. A., Usher D., Brewer H. B., Jr The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate. J Clin Invest. 1994 Jun;93(6):2758–2763. doi: 10.1172/JCI117292. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rader D. J., Hoeg J. M., Brewer H. B., Jr Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease. Ann Intern Med. 1994 Jun 15;120(12):1012–1025. doi: 10.7326/0003-4819-120-12-199406150-00008. [DOI] [PubMed] [Google Scholar]
- Rader D. J., Mann W. A., Cain W., Kraft H. G., Usher D., Zech L. A., Hoeg J. M., Davignon J., Lupien P., Grossman M. The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans. J Clin Invest. 1995 Mar;95(3):1403–1408. doi: 10.1172/JCI117794. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rath M., Niendorf A., Reblin T., Dietel M., Krebber H. J., Beisiegel U. Detection and quantification of lipoprotein(a) in the arterial wall of 107 coronary bypass patients. Arteriosclerosis. 1989 Sep-Oct;9(5):579–592. doi: 10.1161/01.atv.9.5.579. [DOI] [PubMed] [Google Scholar]
- Schwenke D. C., Carew T. E. Initiation of atherosclerotic lesions in cholesterol-fed rabbits. II. Selective retention of LDL vs. selective increases in LDL permeability in susceptible sites of arteries. Arteriosclerosis. 1989 Nov-Dec;9(6):908–918. doi: 10.1161/01.atv.9.6.908. [DOI] [PubMed] [Google Scholar]
- Schwenke D. C., St Clair R. W. Influx, efflux, and accumulation of LDL in normal arterial areas and atherosclerotic lesions of white Carneau pigeons with naturally occurring and cholesterol-aggravated aortic atherosclerosis. Arterioscler Thromb. 1993 Sep;13(9):1368–1381. doi: 10.1161/01.atv.13.9.1368. [DOI] [PubMed] [Google Scholar]
- Schwenke D. C., Zilversmit D. B. Enhanced accumulation and turnover of esterified cholesterol in injured rabbit aorta. Arteriosclerosis. 1987 Jul-Aug;7(4):367–377. doi: 10.1161/01.atv.7.4.367. [DOI] [PubMed] [Google Scholar]
- Schwenke D. C., Zilversmit D. B. The arterial barrier to lipoprotein influx in the hypercholesterolemic rabbit. 1. Studies during the first two days after mild aortic injury. Atherosclerosis. 1989 Jun;77(2-3):91–103. doi: 10.1016/0021-9150(89)90071-3. [DOI] [PubMed] [Google Scholar]
- Smith E. B., Cochran S. Factors influencing the accumulation in fibrous plaques of lipid derived from low density lipoprotein. II. Preferential immobilization of lipoprotein (a) (Lp(a)). Atherosclerosis. 1990 Oct;84(2-3):173–181. doi: 10.1016/0021-9150(90)90088-z. [DOI] [PubMed] [Google Scholar]
- Srinivasan S. R., Vijayagopal P., Dalferes E. R., Jr, Abbate B., Radhakrishnamurthy B., Berenson G. S. Low density lipoprotein retention by aortic tissue. Contribution of extracellular matrix. Atherosclerosis. 1986 Dec;62(3):201–208. doi: 10.1016/0021-9150(86)90094-8. [DOI] [PubMed] [Google Scholar]
- Stary H. C., Chandler A. B., Glagov S., Guyton J. R., Insull W., Jr, Rosenfeld M. E., Schaffer S. A., Schwartz C. J., Wagner W. D., Wissler R. W. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb. 1994 May;14(5):840–856. doi: 10.1161/01.atv.14.5.840. [DOI] [PubMed] [Google Scholar]
- Stender S., Zilversmit D. B. Transfer of plasma lipoprotein components and of plasma proteins into aortas of cholesterol-fed rabbits. Molecular size as a determinant of plasma lipoprotein influx. Arteriosclerosis. 1981 Jan-Feb;1(1):38–49. doi: 10.1161/01.atv.1.1.38. [DOI] [PubMed] [Google Scholar]
- Utermann G., Menzel H. J., Kraft H. G., Duba H. C., Kemmler H. G., Seitz C. Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest. 1987 Aug;80(2):458–465. doi: 10.1172/JCI113093. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wiklund O., Carew T. E., Steinberg D. Role of the low density lipoprotein receptor in penetration of low density lipoprotein into rabbit aortic wall. Arteriosclerosis. 1985 Mar-Apr;5(2):135–141. doi: 10.1161/01.atv.5.2.135. [DOI] [PubMed] [Google Scholar]
- Wootton R., Baskerville P., Turner P., Insell M., Shaikh M., La Ville A., Quiney J., Browse N. L., Lewis B. A method for quantifying lipoprotein flux rates between plasma and arterial intima in vivo. Clin Phys Physiol Meas. 1987 Feb;8(1):65–74. doi: 10.1088/0143-0815/8/1/005. [DOI] [PubMed] [Google Scholar]
- Zilversmit D. B., Shea T. M. Quantitation of apoB-48 and apoB-100 by gel scanning or radio-iodination. J Lipid Res. 1989 Oct;30(10):1639–1646. [PubMed] [Google Scholar]