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Inhibition of Stimulated Prostaglandin Biosynthesis by Retinoic Acid in Smooth Muscle Cells¹

Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02254 [S. M. G., L. L.], and Department of Neurology and Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 [M. A. M.]

Bovine aorta smooth muscle cells (SMC) incubated with a tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), released increased levels of prostaglandin I₂ [measured as its stable hydrolytic product, 6-keto-prostaglandin F₁ (6-keto-PGF₁)], and this response was inhibited by all-trans-retinoic acid (RA) at concentrations as low as 17 nM. Retinol and retinyl acetate, at concentrations as high as 1.7 and 1.5 µM, respectively, did not inhibit the TPA-stimulated 6-keto-PGF₁ production. RA was not cytotoxic at 1.7 µM, as assayed by exclusion of trypan blue dye. Inhibition by RA was increased after preincubation of the SMC with RA prior to TPA stimulation. The inhibition of arachidonic acid (AA) metabolism by RA was not specific for TPA stimulation; RA inhibited prostaglandin production after SMCs were stimulated by serotonin; melittin; the Ca²⁺ ionophore, A23187; and fetal calf serum. RA had no effect on phorbol ester binding to SMC, nor did it inhibit increased 6-keto-PGF₁ production in SMC treated with exogenous AA. While RA inhibited TPA-stimulated production of ¹⁴C-labeled 6-keto-PGF₁ from [¹⁴C]AA-labeled cells, it did not inhibit the accumulation of [¹⁴C]AA in the culture medium. The data suggest that RA inhibits stimulated, rather than basal, levels of prostaglandin production. RA does not seem to act by inhibiting the deacylation of AA from cellular phospholipid pools, insofar as this is reflected in the accumulation of AA in the media, but may inhibit reactions at, or after, the generation of endoperoxides by cyclooxygenase.

¹ This work was supported by Grants GM 27256, CA 17309, and NS 19038-01 from the NIH. Publication No. 1461 of the Department of Biochemistry, Brandeis University, Waltham, Mass. 02254.

² Supported by NIH National Research Service Award AM06999-01.

³ Established Investigator of the American Heart Association.

⁴ American Cancer Society Research Professor of Biochemistry. To whom requests for reprints should be addressed.

Received 5/16/83. Accepted 9/28/83.

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