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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1542.)
© 2007 American Heart Association, Inc.

Vascular Biology

CYP26 Inhibitor R115866 Increases Retinoid Signaling in Intimal Smooth Muscle Cells

Pauline Ocaya; Andreas C. Gidlöf; Peder S. Olofsson; Hans Törmä; Allan Sirsjö

From the Division of Biomedicine, Department of Clinical Medicine (P.O., A.S.), University of Örebro; the Center for Molecular Medicine, Experimental Cardiovascular Research Unit (A.C.G., P.S.O.), Karolinska Institute, Stockholm; and the Department of Medical Sciences/Dermatology (H.T.), Uppsala University, Sweden.

Correspondence to Andreas C. Gidlöf, Center for Molecular Medicine, L8:03, Karolinska Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail andreas.gidlof{at}cmm.ki.se Author to receive reprint requests: Pauline Ocaya, Division of Biomedicine, Department of clinical medicine, University of Örebro, 701 82 Örebro, Sweden.

Objective— Intimal smooth muscle cells (SMCs) are dedifferentiated SMCs that have a powerful ability to proliferate and migrate. This cell-type is responsible for the development of intimal hyperplasia after vascular angioplasty. Retinoids, especially all-trans retinoid acid, are known to regulate many processes activated at sites of vascular injury, including modulation of SMC phenotype and inhibition of SMC proliferation. Intracellular levels of active retinoids are under firm control. A key enzyme is the all-trans retinoic acid-degrading enzyme cytochrome p450 isoform 26 (CYP26). Thus, an alternative approach to exogenous retinoid administration could be to increase the intracellular level of all-trans retinoic acid by blocking CYP26-mediated degradation of retinoids.

Methods and Results— Vascular intimal and medial SMCs expressed CYP26A1 and B1 mRNA. Although medial cells remained unaffected, treatment with the CYP26-inhibitor R115866 significantly increased cellular levels of all-trans retinoic acid in intimal SMCs. The increased levels of all-trans retinoic acid induced retinoid-regulated genes and decreased mitogenesis.

Conclusions— Blocking of the CYP26-mediated catabolism mimics the effects of exogenously administrated active retinoids on intimal SMCs. Therefore, CYP26-inibitors offer a potential new therapeutic approach to vascular proliferative disorders.

atRA regulates proliferation and differentiation of various cell types. We show that inhibition of CYP26 by R115866 in intimal SMCs results in increased cellular retinoids and retinoidal effects, ie, inhibition of DNA synthesis and alteration of cell morphology. Therefore, CYP26 inibitors offer a potential new therapeutic approach to vascular proliferative disorders.

Key Words: retinoids • CYP26 • retinoid metabolism • vascular smooth muscle cells