CYP26B1 plays a major role in the regulation of all-trans-retinoic acid metabolism and signaling in human aortic smooth muscle cells.
OBJECTIVE
The cytochrome P450 enzymes of the CYP26 family are involved in the catabolism of the biologically active retinoid all-trans-retinoic acid (atRA). Since it is possible that an increased local CYP26 activity would reduce the effects of retinoids in vascular injury, we investigated the role of CYP26 in the regulation of atRA levels in human aortic smooth muscle cells (AOSMCs).


METHODS
The expression of CYP26 was investigated in cultured AOSMCs using real-time PCR. The metabolism of atRA was analyzed by high-performance liquid chromatography, and the inhibitor R115866 or small interfering RNA (siRNA) was used to suppress CYP26 activity/expression.


RESULTS
AOSMCs expressed CYP26B1 constitutively and atRA exposure augmented CYP26B1 mRNA levels. Silencing of the CYP26B1 gene expression or reduction of CYP26B1 enzymatic activity by using siRNA or the inhibitor R115866, respectively, increased atRA-mediated signaling and resulted in decreased cell proliferation. The CYP26 inhibitor also induced expression of atRA-responsive genes. Therefore, atRA-induced CYP26 expression accelerated atRA inactivation in AOSMCs, giving rise to an atRA-CYP26 feedback loop. Inhibition of this loop with a CYP26 inhibitor increased retinoid signaling.


CONCLUSIONS
The results suggest that CYP26 inhibitors may be a therapeutic alternative to exogenous retinoid administration.
Ocaya
Pauline Ajok
PA
Division of Biomedicine, Department of Clinical Medicine, Örebro University, Örebro, Sweden.
Elmabsout
Ali Ateia
AA
Olofsson
Peder Stefan
PS
Törmä
Hans
H
Gidlöf
Andreas Carl
AC
Sirsjö
Allan
A
D001011:Aorta / Q000166:cytology*; D052160:Benzothiazoles / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D034741:RNA, Small Interfering; D000072516:Retinoic Acid 4-Hydroxylase; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
D052160:Benzothiazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D034741:RNA, Small Interfering; D014230:Triazoles; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607079:CYP26B1 protein, human; D000072516:Retinoic Acid 4-Hydroxylase; C406527:R 115866