Direct and Endothelial Cell-mediated Effect of Cyclosporin A on the Proliferation of Rat Smooth Muscle Cells in Vitro

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 1993 Jan 1

PMID 8424452

Citations 4

Authors

D Leszczynski

Y Zhao

T J Yeagley

M L Foegh

Affiliations

Soon will be listed here.

Abstract

Cyclosporin A (CsA) has been suggested to potentiate graft vascular disease by stimulation of smooth muscle cell (SMC) proliferation. Both the in vitro and in vivo data are discordant, showing both stimulatory and inhibitory effects of CsA on vascular SMC proliferation. The direct and endothelial cell-mediated effects of CsA on vascular SMC proliferation were examined in vitro using the incorporation of [3H]thymidine. All experiments were done in serum-free conditions. The exposure of SMC to CsA (0.0001 to 0.1 micrograms/ml) had no effect on proliferation. High doses of CsA (0.5 to 10.0 micrograms/ml) were toxic to the SMC and endothelial cells; 90% of SMC population died within 3 to 6 days of exposure to 10.0 micrograms/ml CsA. In the studies on the endothelial cell-mediated effect of CsA, the endothelial cell-conditioned medium (ECCM) significantly increased SMC proliferation. This stimulatory effect was significantly attenuated when the ECCM was obtained from endothelial cells exposed to CsA. Endothelin (ET) is suggested to be an endothelial-cell-derived growth factor for SMC, and implicated as a possible cause of the uncontrolled proliferation of SMC during development of graft vascular disease. Exposure of SMC to levels of recombinant ET similar to the levels found in the ECCM (0.19 + 0.01 pg/ml) significantly increased SMC proliferation. CsA increased fivefold ET concentration in the ECCM. However, despite this rise in ET levels, there was a 45% decrease in SMC proliferation. In conclusion, CsA does not exert a direct modulatory effect on SMC proliferation in vitro, but may inhibit SMC proliferation indirectly via endothelial cell-derived factors. These unidentified factor(s) inhibit SMC proliferation and abolish the mitogenic effect of ET on SMC.

Citing Articles

The effect of small bowel transplantation on the morphology and physiology of intestinal muscle: a comparison of autografts versus allografts in dogs.

Sugitani A, Bauer A, Reynolds J, Halfter W, Nomoto M, Starzl T Transplantation. 1997; 63(2):186-94.

PMID: 9020316 PMC: 3154774. DOI: 10.1097/00007890-199701270-00003.

CD4+ mononuclear cells induce cytokine expression, vascular smooth muscle cell proliferation, and arterial occlusion after endothelial injury.

Hancock W, Adams D, Wyner L, Sayegh M, Karnovsky M Am J Pathol. 1994; 145(5):1008-14.

PMID: 7977633 PMC: 1887438.

Prominence of coronary arterial wall lipids in human heart allografts. Implications for pathogenesis of allograft arteriopathy.

McManus B, Horley K, Wilson J, Malcom G, Kendall T, Miles R Am J Pathol. 1995; 147(2):293-308.

PMID: 7639327 PMC: 1869807.

Apoptosis of vascular smooth muscle cells. Protein kinase C and oncoprotein Bcl-2 are involved in regulation of apoptosis in non-transformed rat vascular smooth muscle cells.

Leszczynski D, Zhao Y, Luokkamaki M, Foegh M Am J Pathol. 1994; 145(6):1265-70.

PMID: 7527616 PMC: 1887488.

References

Bunchman T, Brookshire C . Cyclosporine-induced synthesis of endothelin by cultured human endothelial cells. J Clin Invest. 1991; 88(1):310-4. PMC: 296034. DOI: 10.1172/JCI115293. View

Ferns G, Reidy M, Ross R . Vascular effects of cyclosporine A in vivo and in vitro. Am J Pathol. 1990; 137(2):403-13. PMC: 1877614. View

Thyberg J, Hansson G . Cyclosporine A inhibits induction of DNA synthesis by PDGF and other peptide mitogens in cultured rat aortic smooth muscle cells and dermal fibroblasts. Growth Factors. 1991; 4(3):209-19. DOI: 10.3109/08977199109104817. View

Harlan J, Harker L, Reidy M, Gajdusek C, Schwartz S, Striker G . Lipopolysaccharide-mediated bovine endothelial cell injury in vitro. Lab Invest. 1983; 48(3):269-74. View

Harlan J, Harker L, Striker G, Weaver L . Effects of lipopolysaccharide on human endothelial cells in culture. Thromb Res. 1983; 29(1):15-26. DOI: 10.1016/0049-3848(83)90121-4. View

LINDSEY J, Morisaki N, Stitts J, Zager R, Cornwell D . Fatty acid metabolism and cell proliferation: IV. Effect of prostanoid biosynthesis from endogenous fatty acid release with cyclosporin-A. Lipids. 1983; 18(8):566-9. DOI: 10.1007/BF02535399. View

. Renal histopathology in kidney transplant recipients immunosuppressed with cyclosporin A: results of an international workshop. Clin Nephrol. 1985; 24(3):107-19. View

Yoshimura N, Oka T, Ohmori Y, Aikawa I, Fukuda M, Kahan B . Influence of in vivo cyclosporine on interleukin production in kidney transplant recipients. Transplant Proc. 1987; 19(1 Pt 2):1194-8. View

Yoshimura N, Oka T, Clark S, Kahan B . The inhibition of interleukin 2 (IL-2) gene expression at the level of messenger RNA by in vivo cyclosporine treatment in kidney transplant recipients. Transplant Proc. 1987; 19(4):3510-2. View

10.

Muskett A, Burton N, Eichwald E, Shelby J, Hendrickson M, Sullivan J . The effect of antiplatelet drugs on graft atherosclerosis in rat heterotopic cardiac allografts. Transplant Proc. 1987; 19(4 Suppl 5):74-6. View

11.

Libby P, Warner S, FRIEDMAN G . Interleukin 1: a mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids. J Clin Invest. 1988; 81(2):487-98. PMC: 329596. DOI: 10.1172/JCI113346. View

12.

Flavin M, Parton L, Bowman C . Conditioned medium from irradiated bovine pulmonary artery endothelial cells stimulates increased protein synthesis by irradiated bovine lung fibroblasts in vitro. Exp Lung Res. 1990; 16(5):405-22. DOI: 10.3109/01902149009068817. View

13.

Thyberg J, Hedin U, Sjolund M, Palmberg L, Bottger B . Regulation of differentiated properties and proliferation of arterial smooth muscle cells. Arteriosclerosis. 1990; 10(6):966-90. DOI: 10.1161/01.atv.10.6.966. View

14.

Yoshimura N, Kahan B, Oka T . The in vivo effect of cyclosporine on interleukin-6 gene expression in renal transplant recipients. Transplant Proc. 1991; 23(1 Pt 2):958-60. View

15.

Jonasson L, Holm J, Hansson G . Cyclosporin A inhibits smooth muscle proliferation in the vascular response to injury. Proc Natl Acad Sci U S A. 1988; 85(7):2303-6. PMC: 279979. DOI: 10.1073/pnas.85.7.2303. View

16.

BARNHART G, Pascoe E, Mills A, Szentpetery S, Eich D, Mohanakumar T . Accelerated coronary arteriosclerosis in cardiac transplant recipients. Transplant Rev (Orlando). 1987; 1:31-46. DOI: 10.1016/s0955-470x(87)80004-6. View

17.

Komuro I, Kurihara H, Sugiyama T, Yoshizumi M, Takaku F, Yazaki Y . Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth muscle cells. FEBS Lett. 1988; 238(2):249-52. DOI: 10.1016/0014-5793(88)80489-7. View

18.

Diglio C, Grammas P, Giacomelli F, Wiener J . Rat heart-derived endothelial and smooth muscle cell cultures: isolation, cloning and characterization. Tissue Cell. 1988; 20(4):477-92. DOI: 10.1016/0040-8166(88)90051-1. View

19.

Yoshimura N, Oka T, Kita M, Teraoka H, Hirai Y . Combination therapy of cyclosporine with steroid inhibits gamma-interferon and interleukin-1 gene expression at the level of mRNA synthesis in vivo. J Clin Immunol. 1989; 9(4):322-8. DOI: 10.1007/BF00918664. View

20.

Hansson G, Jonasson L, Seifert P, Stemme S . Immune mechanisms in atherosclerosis. Arteriosclerosis. 1989; 9(5):567-78. DOI: 10.1161/01.atv.9.5.567. View