CYP26 inhibitor R115866 increases retinoid signaling in intimal smooth muscle cells.
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.


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-inhibitors offer a potential new therapeutic approach to vascular proliferative disorders.
Ocaya
Pauline
P
Division of Biomedicine, Department of Clinical Medicine, University of Orebro, 701 82 Orebro, Sweden.
Gidlöf
Andreas C
AC
Olofsson
Peder S
PS
Törmä
Hans
H
Sirsjö
Allan
A
D000704:Analysis of Variance; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D052160:Benzothiazoles / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004195:Disease Models, Animal; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D011336:Probability; D020033:Protein Isoforms; D051381:Rats; D017207:Rats, Sprague-Dawley; D012176:Retinoids / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D014230:Triazoles / Q000494:pharmacology*; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism*; D017540:Tunica Media / Q000187:drug effects / Q000378:metabolism
D052160:Benzothiazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D020033:Protein Isoforms; D012176:Retinoids; D014230:Triazoles; D003577:Cytochrome P-450 Enzyme System; C406527:R 115866