Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1980 May;65(5):967–981. doi: 10.1172/JCI109783

Suppression of experimental atherosclerosis by the Ca++-antagonist lanthanum. Possible role of calcium in atherogenesis.

D M Kramsch, A J Aspen, C S Apstein
PMCID: PMC371426  PMID: 7364947

Abstract

Agents inhibiting calcium deposition into arteries are known to suppress atherosclerosis in animals. However, the precise role of calcium in atherogenesis is unknown. In this study, the specific Ca2+-antagonist lanthanum was used to attempt suppression of experimental atherosclerosis and to gain more insight into the possible effects of calcium on atherogenesis. Rabbits were fed an atherogenic diet with and without increasing doses of LaCl3. All cholesterol-fed rabbits showed marked increases in serum cholesterol and ca2+. Untreated atherogenic animals revealed pronounced gross and microscopic atherosclerosis and striking increases in the aortic content of cholesterol, collagen, "elastin," and calcium as well as of elastin calcium, polar amino acids, and cholesterol. With increasing LaCl3 dosage these abnormalities progressively decreased and were completely abolished at the highest dose. The ingested La3+ was absorbed only in small quantities and had no discernible effect on the calcium and connective tissue content of bone, skin, lung, heart, and skeletal muscle nor on myocardial function (left ventricle pressure and left ventricle dp/dt) or myocardial and muscle content in ATP and creatine phosphate. The data suggest that shifts in arterial Ca2+-distribution may play a decisive part in atherogenesis, and provision of arterial calcium homeostasis by La3+ a pivotal role in its prevention, despite hypercholesteremia. Other inhibitors of calcium deposition into arteries may exert their protective effect by similar mechanisms. However, a direct inhibition of atherogenesis by La3+ cannot entirely be ruled out in this study, although no direct effects of La3+ on tissue metabolism have as yet been reported.

Full text

PDF
968

Images in this article

972Image
on p.972
973Image
on p.973
971Image
on p.971
974Image
on p.974
975Image
on p.975

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bergman I., Loxley R. Lung tissue hydrolysates: studies of the optimum conditions for the spectrophotometric determination of hydroxyproline. Analyst. 1969 Jul;94(120):575–584. doi: 10.1039/an9699400575. [DOI] [PubMed] [Google Scholar]
  2. Berridge M. J. The interaction of cyclic nucleotides and calcium in the control of cellular activity. Adv Cyclic Nucleotide Res. 1975;6:1–98. [PubMed] [Google Scholar]
  3. Boucek M. M., Snyderman R. Calcium influx requirement for human neutrophil chemotaxis: inhibition by lanthanum chloride. Science. 1976 Sep 3;193(4256):905–907. doi: 10.1126/science.948752. [DOI] [PubMed] [Google Scholar]
  4. Chan C. T., Wells H., Kramsch D. M. Suppression of calcific fibrous-fatty plaque formation in rabbits by agents not affecting elevated serum cholesterol levels. The effect of thiophene compounds. Circ Res. 1978 Jul;43(1):115–125. doi: 10.1161/01.res.43.1.115. [DOI] [PubMed] [Google Scholar]
  5. D'Amore P., Shepro D. Stimulation of growth and calcium influx in cultured, bovine, aortic endothelial cells by platelets and vasoactive substances. J Cell Physiol. 1977 Aug;92(2):177–183. doi: 10.1002/jcp.1040920206. [DOI] [PubMed] [Google Scholar]
  6. Downing D. T. Photodensitometry in the thin-layer chromatographic analysis of neutral lipids. J Chromatogr. 1968 Nov 5;38(1):91–99. doi: 10.1016/0021-9673(68)85011-3. [DOI] [PubMed] [Google Scholar]
  7. Fassina G. Mechanisms of lipomobilization. Adv Exp Med Biol. 1978;109:209–223. doi: 10.1007/978-1-4684-0967-3_11. [DOI] [PubMed] [Google Scholar]
  8. Fuchs C., Dorn D., McIntosh C., Scheler F., Kraft B. Comparative calcium ion determinations in plasma and whole blood with a new calcium ion analyzer. Clin Chim Acta. 1976 Feb 16;67(1):99–102. doi: 10.1016/0009-8981(76)90222-9. [DOI] [PubMed] [Google Scholar]
  9. Grant M. E., Prockop D. J. The biosynthesis of collagen. 3. N Engl J Med. 1972 Feb 10;286(6):291–300. doi: 10.1056/NEJM197202102860604. [DOI] [PubMed] [Google Scholar]
  10. Guilland D. F., Sallis J. D., Fleisch H. The effect of two diphosphonates on the handling of calcium by rat kidney mitochondria in vitro. Calcif Tissue Res. 1974;15(4):303–314. doi: 10.1007/BF02059065. [DOI] [PubMed] [Google Scholar]
  11. Helin P., Lorenzen I., Garbarsch C., Matthiessen M. E. Repair in arterial tissue. Morphological and biochemical changes in rabbit aorta after a single dilatation injury. Circ Res. 1971 Nov;29(5):542–554. doi: 10.1161/01.res.29.5.542. [DOI] [PubMed] [Google Scholar]
  12. Hellman B., Sehlin J., Täljedal I. B. Calcium and secretion: distinction between two pools of glucose-sensitive calcium in pancreatic islets. Science. 1976 Dec 24;194(4272):1421–1423. doi: 10.1126/science.795030. [DOI] [PubMed] [Google Scholar]
  13. Hollander W., Prusty S., Nagraj S., Kirkpatrick B., Paddock J., Colombo M. Comparative effects of cetaben (PHB) and dichlormethylene diphosphonate (Cl2MDP) on the development of atherosclerosis in the cynomolgus monkey. Atherosclerosis. 1978 Nov;31(3):307–325. doi: 10.1016/0021-9150(78)90066-7. [DOI] [PubMed] [Google Scholar]
  14. Hornebeck W., Partridge S. M. Conformational changes in fibrous elastin due to calcium ions. Eur J Biochem. 1975 Feb 3;51(1):73–78. doi: 10.1111/j.1432-1033.1975.tb03908.x. [DOI] [PubMed] [Google Scholar]
  15. Keeley F. W., Fagan D. G., Webster S. I. Quantity and character of elastin in developing human lung parenchymal tissues of normal infants and infants with respiratory distress syndrome. J Lab Clin Med. 1977 Dec;90(6):981–989. [PubMed] [Google Scholar]
  16. Keeley F. W., Partridge S. M. Amino acid composition and calcification of human aortic elastin. Atherosclerosis. 1974 Mar-Apr;19(2):287–296. doi: 10.1016/0021-9150(74)90063-x. [DOI] [PubMed] [Google Scholar]
  17. Kivirikko K. I. Urinary excretion of hydroxyproline in health and disease. Int Rev Connect Tissue Res. 1970;5:93–163. doi: 10.1016/b978-0-12-363705-5.50008-7. [DOI] [PubMed] [Google Scholar]
  18. Kramsch D. M., Chan C. T. The effect of agents interfering with soft tissue calcification and cell proliferation on calcific fibrous-fatty plaques in rabbits. Circ Res. 1978 Apr;42(4):562–571. doi: 10.1161/01.res.42.4.562. [DOI] [PubMed] [Google Scholar]
  19. Kramsch D. M., Franzblau C. Biochemistry of collagen and elastic fibers in atherosclerotic lesions. Adv Exp Med Biol. 1977;82:774–781. doi: 10.1007/978-1-4613-4220-5_155. [DOI] [PubMed] [Google Scholar]
  20. Kramsch D. M., Franzblau C., Hollander W. The protein and lipid composition of arterial elastin and its relationship to lipid accumulation in the atherosclerotic plaque. J Clin Invest. 1971 Aug;50(8):1666–1677. doi: 10.1172/JCI106656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kramsch D. M., Hollander W. The interaction of serum and arterial lipoproteins with elastin of the arterial intima and its role in the lipid accumulation in atherosclerotic plaques. J Clin Invest. 1973 Feb;52(2):236–247. doi: 10.1172/JCI107180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kramsch D. M. The role of connective tissue in atherosclerosis. Adv Exp Med Biol. 1978;109:155–194. doi: 10.1007/978-1-4684-0967-3_9. [DOI] [PubMed] [Google Scholar]
  23. Kritchevsky D., Tepper S. A., Vesselinovitch D., Wissler R. W. Cholesterol vehicle in experimental atherosclerosis. 11. Peanut oil. Atherosclerosis. 1971 Jul-Aug;14(1):53–64. doi: 10.1016/0021-9150(71)90038-4. [DOI] [PubMed] [Google Scholar]
  24. LANSING A. I., ROSENTHAL T. B., ALEX M., DEMPSEY E. W. The structure and chemical characterization of elastic fibers as revealed by elastase and by electron microscopy. Anat Rec. 1952 Dec;114(4):555–575. doi: 10.1002/ar.1091140404. [DOI] [PubMed] [Google Scholar]
  25. Lloyd W., Fang V. S., Wells H., Tashjian A. H., Jr 2-Thiophenecarboxylic acid: a hypoglycemic, antilipolytic agent with hypocalcemic and hypophosphatemic effects in rats. Endocrinology. 1969 Oct;85(4):763–768. doi: 10.1210/endo-85-4-763. [DOI] [PubMed] [Google Scholar]
  26. Minkin C., Rabadjija L., Goldhaber P. Bone remodeling in vitro: the effects of two diphosphonates on osteoid synthesis and bone resorption in mouse calvaria. Calcif Tissue Res. 1974;14(2):161–168. doi: 10.1007/BF02060292. [DOI] [PubMed] [Google Scholar]
  27. Morrison L. M., Bajwa G. S., Alfin-Slater R. B., Ershoff B. H. Prevention of vascular lesions by chondroitin sulfate A in the coronary artery and aorta of rats induced by a hypervitaminosis D, cholesterol-containing diet. Atherosclerosis. 1972 Jul-Aug;16(1):105–118. doi: 10.1016/0021-9150(72)90013-5. [DOI] [PubMed] [Google Scholar]
  28. Mustard J. F., Packham M. A. Thromboembolism: a manifestation of the response of blood to injury. Circulation. 1970 Jul;42(1):1–21. doi: 10.1161/01.cir.42.1.1. [DOI] [PubMed] [Google Scholar]
  29. Numano F., Watanabe Y., Takeno K., Takano T., Arita M., Numano F., Maezawa H., Shimamoto T., Adachi K. Microassay of cylic nucleotides in vessel wall. I. Cyclic AMP. Exp Mol Pathol. 1976 Oct;25(2):172–181. doi: 10.1016/0014-4800(76)90027-7. [DOI] [PubMed] [Google Scholar]
  30. Packham M. A., Cazenave J. P., Kinlough-Rathbone R. L., Mustard J. F. Drug effects on platelet adherence to collagen and damaged vessel walls. Adv Exp Med Biol. 1978;109:253–276. doi: 10.1007/978-1-4684-0967-3_14. [DOI] [PubMed] [Google Scholar]
  31. Potokar M., Schmidt-Dunker M. The inhibitory effect of new diphosphonic acids on aortic and kidney calcification in vivo. Atherosclerosis. 1978 Aug;30(4):313–320. doi: 10.1016/0021-9150(78)90124-7. [DOI] [PubMed] [Google Scholar]
  32. Radhakrishnamurthy B., Ruiz H. A., Jr, Berenson G. S. Isolation and characterization of proteoglycans from bovine aorta. J Biol Chem. 1977 Jul 25;252(14):4831–4841. [PubMed] [Google Scholar]
  33. Robert B., Szigeti M., Derouette J. C., Robert L. Studies on the nature of the "microfibrillar" component of elastic fibers. Eur J Biochem. 1971 Aug 25;21(4):507–516. doi: 10.1111/j.1432-1033.1971.tb01496.x. [DOI] [PubMed] [Google Scholar]
  34. Rosenblum I. Y., Black H. E., Ferrell J. F. The effects of various diphosphonates on a rat model of cardiac calciphylaxis. Calcif Tissue Res. 1977 Jun 28;23(2):151–159. doi: 10.1007/BF02012781. [DOI] [PubMed] [Google Scholar]
  35. Rosenblum I. Y., Flora L., Eisenstein R. The effect of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) on a rabbit model of athero-arteriosclerosis. Atherosclerosis. 1975 Nov-Dec;22(3):411–424. doi: 10.1016/0021-9150(75)90021-0. [DOI] [PubMed] [Google Scholar]
  36. Ross R., Glomset J. A. The pathogenesis of atherosclerosis (second of two parts). N Engl J Med. 1976 Aug 19;295(8):420–425. doi: 10.1056/NEJM197608192950805. [DOI] [PubMed] [Google Scholar]
  37. Srinivasan S. R., Lopez A., Radhakrishnamurthy B., Berenson G. S. Complexing of serum pre-beta and beta-lipoproteins and acid mucopolysaccharides. Atherosclerosis. 1970 Nov-Dec;12(3):321–334. doi: 10.1016/0021-9150(70)90036-5. [DOI] [PubMed] [Google Scholar]
  38. Urry D. W., Cunningham W. D., Onishi T. A neutral polypeptide--calcium ion complex. Biochim Biophys Acta. 1973 Apr 5;292(3):853–857. doi: 10.1016/0005-2728(73)90035-2. [DOI] [PubMed] [Google Scholar]
  39. Wartman A., Lampe T. L., McCann D. S., Boyle A. J. Plaque reversal with MgEDTA in experimental atherosclerosis: elastin and collagen metabolism. J Atheroscler Res. 1967 May-Jun;7(3):331–341. doi: 10.1016/s0368-1319(67)80060-7. [DOI] [PubMed] [Google Scholar]
  40. Werb Z., Gordon S. Elastase secretion by stimulated macrophages. Characterization and regulation. J Exp Med. 1975 Aug 1;142(2):361–377. doi: 10.1084/jem.142.2.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Whittington-Coleman P. J., Carrier O., Jr, Douglas B. H. The effects of propranolol on cholesterol-induced atheromatous lesions. Atherosclerosis. 1973 Sep-Oct;18(2):337–345. doi: 10.1016/0021-9150(73)90109-3. [DOI] [PubMed] [Google Scholar]
  42. Whittington-Coleman P. J., Carrier O., Jr Effects of agents altering vascular calcium in experimental atherosclerosis. Atherosclerosis. 1970 Jul-Aug;12(1):15–24. doi: 10.1016/0021-9150(70)90079-1. [DOI] [PubMed] [Google Scholar]
  43. Wolinsky H., Daly M. M. A method for the isolation of intima-media samples from arteries. Proc Soc Exp Biol Med. 1970 Nov;135(2):364–368. doi: 10.3181/00379727-135-35052. [DOI] [PubMed] [Google Scholar]
  44. Wybenga D. R., Pileggi V. J., Dirstine P. H., Di Giorgio J. Direct manual determination of serum total cholesterol with a single stable reagent. Clin Chem. 1970 Dec;16(12):980–984. [PubMed] [Google Scholar]
  45. YU S. Y., BLUMENTHAL H. T. The calcification of elastic fibers. I. Biochemical studies. J Gerontol. 1963 Apr;18:119–126. doi: 10.1093/geronj/18.2.119. [DOI] [PubMed] [Google Scholar]
  46. Yu S. Y., Yoshida A. The fate of 14C-elastin in the peritoneal cavity of rats. I. Biochemical studies. Lab Invest. 1977 Aug;37(2):143–149. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES