Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1985 May;75(5):1554–1558. doi: 10.1172/JCI111860

Nifedipine increases cholesteryl ester hydrolytic activity in lipid-laden rabbit arterial smooth muscle cells. A possible mechanism for its antiatherogenic effect.

O R Etingin, D P Hajjar
PMCID: PMC425495  PMID: 3923040

Abstract

Calcium and cholesterol (CHOL) accumulation are characteristic features of human atherosclerotic plaques. Calcium channel blockers have been shown to increase calcium levels in myocardial cells and suppress free and esterified CHOL deposition in arteries of CHOL-fed animals. To test the hypothesis that Nifedipine alters CHOL metabolism, thereby decreasing free and esterified CHOL accumulation in smooth muscle cells (SMC), we cultured arterial SMC from rabbits fed a normal or egg-supplemented diet for 6 mo. Cultured cells were treated with 0.1 mg/liter Nifedipine every 3 d during a 1-wk experiment. Although Nifedipine significantly increased lysosomal and cytoplasmic cholesteryl ester (CE) hydrolase activity in normal SMC via increased levels of intracellular cyclic AMP, no change in total CHOL content was observed after 1 wk of Nifedipine treatment. Contrary to these observations, lipid-laden SMC demonstrated a significant 50% loss in CHOL and CE after treatment with Nifedipine, due in part to the observed increase in CE hydrolytic activities. These data support our hypothesis that Nifedipine decreases CHOL and CE accumulation in arterial SMC by increasing arterial CE hydrolysis.

Full text

PDF
1554

Selected References

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

  1. Adelstein R. S., Conti M. A., Hathaway D. R., Klee C. B. Phosphorylation of smooth muscle myosin light chain kinase by the catalytic subunit of adenosine 3': 5'-monophosphate-dependent protein kinase. J Biol Chem. 1978 Dec 10;253(23):8347–8350. [PubMed] [Google Scholar]
  2. 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]
  3. Coffey R. G., Hadden E. M., Hadden J. W. Phytohemagglutinin stimulation of guanylate cyclase in human lymphocytes. J Biol Chem. 1981 May 10;256(9):4418–4424. [PubMed] [Google Scholar]
  4. 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]
  5. Ginsburg R., Davis K., Bristow M. R., McKennett K., Kodsi S. R., Billingham M. E., Schroeder J. S. Calcium antagonists suppress atherogenesis in aorta but not in the intramural coronary arteries of cholesterol-fed rabbits. Lab Invest. 1983 Aug;49(2):154–158. [PubMed] [Google Scholar]
  6. Hajjar D. P., Falcone D. J., Fowler S., Minick C. R. Endothelium modifies the altered metabolism of the injured aortic wall. Am J Pathol. 1981 Jan;102(1):28–39. [PMC free article] [PubMed] [Google Scholar]
  7. Hajjar D. P., Minick C. R., Fowler S. Arterial neutral cholesteryl esterase. A hormone-sensitive enzyme distinct from lysosomal cholesteryl esterase. J Biol Chem. 1983 Jan 10;258(1):192–198. [PubMed] [Google Scholar]
  8. Hajjar D. P., Weksler B. B., Falcone D. J., Hefton J. M., Tack-Goldman K., Minick C. R. Prostacyclin modulates cholesteryl ester hydrolytic activity by its effect on cyclic adenosine monophosphate in rabbit aortic smooth muscle cells. J Clin Invest. 1982 Sep;70(3):479–488. doi: 10.1172/JCI110639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hajjar D. P., Weksler B. B. Metabolic activity of cholesteryl esters in aortic smooth muscle cells is altered by prostaglandins I2 and E2. J Lipid Res. 1983 Sep;24(9):1176–1185. [PubMed] [Google Scholar]
  10. Hajjar D. P., Wight T. N., Smith S. C. Lipid accumulation and ultrastructural change within the aortic wall during early spontaneous atherogenesis. Am J Pathol. 1980 Sep;100(3):683–705. [PMC free article] [PubMed] [Google Scholar]
  11. Haley N. J., Fowler S., de Duve C. Lysosomal acid cholesteryl esterase activity in normal and lipid-laden aortic cells. J Lipid Res. 1980 Nov;21(8):961–969. [PubMed] [Google Scholar]
  12. Hara A., Radin N. S. Lipid extraction of tissues with a low-toxicity solvent. Anal Biochem. 1978 Oct 1;90(1):420–426. doi: 10.1016/0003-2697(78)90046-5. [DOI] [PubMed] [Google Scholar]
  13. Henry P. D., Bentley K. I. Suppression of atherogenesis in cholesterol-fed rabbit treated with nifedipine. J Clin Invest. 1981 Nov;68(5):1366–1369. doi: 10.1172/JCI110384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hojnacki J. L., Smith S. C. Separation of six lipid classes on one thin-layer chromatogram. J Chromatogr. 1974 Apr 10;90(2):364–367. doi: 10.1016/s0021-9673(00)92542-1. [DOI] [PubMed] [Google Scholar]
  15. Khoo J. C., Mahoney E. M., Steinberg D. Neutral cholesterol esterase activity in macrophages and its enhancement by cAMP-dependent protein kinase. J Biol Chem. 1981 Dec 25;256(24):12659–12661. [PubMed] [Google Scholar]
  16. Kramsch D. M., Aspen A. J., Apstein C. S. Suppression of experimental atherosclerosis by the Ca++-antagonist lanthanum. Possible role of calcium in atherogenesis. J Clin Invest. 1980 May;65(5):967–981. doi: 10.1172/JCI109783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. 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]
  20. Naghshineh S., Treadwell C. R., Gallo L., Vahouny G. V. Activation of adrenal sterol ester hydrolase by dibutyryl cAMP and protein kinase. Biochem Biophys Res Commun. 1974 Dec 11;61(3):1076–1082. doi: 10.1016/0006-291x(74)90265-4. [DOI] [PubMed] [Google Scholar]
  21. Nicolosi R. J., Smith S. C., Santerre R. F. Simultaneous fluorometric analysis of five lipid classes on thin-layer chromatograms. J Chromatogr. 1971 Aug 5;60(1):111–117. [PubMed] [Google Scholar]
  22. Numano F., Maezawa H. Changes of cyclic-AMP and cycic-AMP phosphodiesterase in the progression and regression of experimental atherosclerosis. Ann N Y Acad Sci. 1976;275:311–320. doi: 10.1111/j.1749-6632.1976.tb43363.x. [DOI] [PubMed] [Google Scholar]
  23. Peters T. J., Müller M., De Duve C. Lysosomes of the arterial wall. I. Isolation and subcellular fractionation of cells from normal rabbit aorta. J Exp Med. 1972 Nov 1;136(5):1117–1139. doi: 10.1084/jem.136.5.1117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ranganathan S., Harmony J. A., Jackson R. J. Effect of Ca2+ blocking agents on the metabolism of low density lipoproteins in human skin fibroblasts. Biochem Biophys Res Commun. 1982 Jul 16;107(1):217–224. doi: 10.1016/0006-291x(82)91691-6. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Ross R. The smooth muscle cell. II. Growth of smooth muscle in culture and formation of elastic fibers. J Cell Biol. 1971 Jul;50(1):172–186. doi: 10.1083/jcb.50.1.172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rouleau J. L., Parmley W. W., Stevens J., Wikman-Coffelt J., Sievers R., Mahley R. W., Havel R. J. Verapamil suppresses atherosclerosis in cholesterol-fed rabbits. J Am Coll Cardiol. 1983 Jun;1(6):1453–1460. doi: 10.1016/s0735-1097(83)80049-7. [DOI] [PubMed] [Google Scholar]
  28. Sharma H. M., Geer J. C. Experimental aortic lesions of acute serum sickness in rabbits. Am J Pathol. 1977 Aug;88(2):255–266. [PMC free article] [PubMed] [Google Scholar]
  29. Singh B. N., Hecht H. S., Nademanee K., Chew C. Y. Electrophysiologic and hemodynamic effects of slow-channel blocking drugs. Prog Cardiovasc Dis. 1982 Sep-Oct;25(2):103–132. doi: 10.1016/0033-0620(82)90023-8. [DOI] [PubMed] [Google Scholar]
  30. Stender S., Stender I., Nordestgaard B., Kjeldsen K. No effect of nifedipine on atherogenesis in cholesterol-fed rabbits. Arteriosclerosis. 1984 Jul-Aug;4(4):389–394. doi: 10.1161/01.atv.4.4.389. [DOI] [PubMed] [Google Scholar]
  31. Takano T., Black W. J., Peters T. J., de Duve C. Assay, kinetics, and lysosomal localization of an acid cholesteryl esterase in rabbit aortic smooth muscle cells. J Biol Chem. 1974 Nov 10;249(21):6732–6737. [PubMed] [Google Scholar]
  32. Van Niekerk J. L., Hendriks T., De Boer H. H., Van 't Laar A. Does nifedipine suppress atherogenesis in WHHL rabbits? Atherosclerosis. 1984 Oct;53(1):91–98. doi: 10.1016/0021-9150(84)90109-6. [DOI] [PubMed] [Google Scholar]
  33. Williams M. T., Clark M. R., Ling W. Y., LeMaire W. J., Caron M. G., Marsh J. M. Role of cyclic AMP in the actions of luteinizing hormone on steroidogenesis in the corpus luteum. Adv Cyclic Nucleotide Res. 1978;9:573–582. [PubMed] [Google Scholar]

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

RESOURCES