PMID- 16179585
OWN - NLM
STAT- MEDLINE
DCOM- 20051207
LR  - 20181201
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Linking)
VI  - 97
IP  - 9
DP  - 2005 Oct 28
TI  - Modulation of the Ca2 permeable cation channel TRPV4 by cytochrome P450 
      epoxygenases in vascular endothelium.
PG  - 908-15
AB  - TRPV4 is a broadly expressed Ca2+-permeable cation channel in the vanilloid 
      subfamily of transient receptor potential channels. TRPV4 gates in response to a 
      large variety of stimuli, including cell swelling, warm temperatures, the 
      synthetic phorbol ester 4alpha-phorbol 12,13-didecanoate (4alpha-PDD), and the 
      endogenous lipid arachidonic acid (AA). Activation by cell swelling and AA 
      requires cytochrome P450 (CYP) epoxygenase activity to convert AA to 
      epoxyeicosatrienoic acids (EETs) such as 5,6-EET, 8,9-EET, which both act as 
      direct TRPV4 agonists. To evaluate the role of TRPV4 and its modulation by the 
      CYP pathway in vascular endothelial cells, we performed Ca2+ imaging and 
      patch-clamp measurements on mouse aortic endothelial cells (MAECs) isolated from 
      wild-type and TRPV4(-/-) mice. All TRPV4-activating stimuli induced robust Ca2+ 
      responses in wild-type MAECs but not in MAECs isolated from TRPV4(-/-) mice. 
      Upregulation of CYP2C expression by preincubation with nifedipine enhanced the 
      responses to AA and cell swelling in wild-type MAECs, whereas responses to other 
      stimuli remained unaffected. Conversely, inhibition of CYP2C9 activity with 
      sulfaphenazole abolished the responses to AA and hypotonic solution (HTS). 
      Moreover, suppression of EET hydrolysis using 1-adamantyl-3-cyclo-hexylurea or 
      indomethacin, inhibitors of soluble epoxide hydrolases (sEHs), and 
      cyclooxygenases, respectively, enhanced the TRPV4-dependent responses to AA, HTS, 
      and EETs but not those to 4alpha-PDD or heat. Together, our data establish that 
      CYP-derived EETs modulate the activity of TRPV4 channels in endothelial cells and 
      shows the unraveling of novel modulatory pathways via CYP2C modulation and sEH 
      inhibition.
FAU - Vriens, J
AU  - Vriens J
AD  - Department of Physiology, Campus Gasthuisberg, KU Leuven, Belgium.
FAU - Owsianik, G
AU  - Owsianik G
FAU - Fisslthaler, B
AU  - Fisslthaler B
FAU - Suzuki, M
AU  - Suzuki M
FAU - Janssens, A
AU  - Janssens A
FAU - Voets, T
AU  - Voets T
FAU - Morisseau, C
AU  - Morisseau C
FAU - Hammock, B D
AU  - Hammock BD
FAU - Fleming, I
AU  - Fleming I
FAU - Busse, R
AU  - Busse R
FAU - Nilius, B
AU  - Nilius B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20050922
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (TRPV Cation Channels)
RN  - 0 (Trpv4 protein, mouse)
RN  - 0 (cytochrome P-450 CYP2C subfamily)
RN  - 81246-84-6 (5,6-epoxy-8,11,14-eicosatrienoic acid)
RN  - 81246-85-7 (8,9-epoxyeicosatrienoic acid)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
RN  - FC398RK06S (8,11,14-Eicosatrienoic Acid)
RN  - I9ZF7L6G2L (Nifedipine)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - 8,11,14-Eicosatrienoic Acid/analogs & derivatives/metabolism
MH  - Animals
MH  - Calcium/*metabolism
MH  - Cells, Cultured
MH  - Cytochrome P-450 Enzyme System/*physiology
MH  - Endothelial Cells/*metabolism
MH  - Epoxide Hydrolases/antagonists & inhibitors/*physiology
MH  - Mice
MH  - Nifedipine/pharmacology
MH  - TRPV Cation Channels/*physiology
EDAT- 2005/09/24 09:00
MHDA- 2005/12/13 09:00
CRDT- 2005/09/24 09:00
PHST- 2005/09/24 09:00 [pubmed]
PHST- 2005/12/13 09:00 [medline]
PHST- 2005/09/24 09:00 [entrez]
AID - 01.RES.0000187474.47805.30 [pii]
AID - 10.1161/01.RES.0000187474.47805.30 [doi]
PST - ppublish
SO  - Circ Res. 2005 Oct 28;97(9):908-15. doi: 10.1161/01.RES.0000187474.47805.30. Epub 
      2005 Sep 22.