Cytochrome P450-derived epoxyeicosatrienoic acids and pulmonary hypertension: central role of transient receptor potential C6 channels.
Hypoxia induces the constriction of pulmonary resistance arteries, which results in the redistribution of blood from poor to better ventilated areas, thus optimizing its oxygenation. Many different oxygen-sensing mechanisms have been proposed to regulate this process, including cytochrome P450 enzymes. These enzymes, which convert substrates such as arachidonic acid into bioactive epoxides (the epoxyeicosatrienoic acids [EETs]), are highly expressed in the lung as is the soluble epoxide hydrolase which metabolizes the epoxides to their less active diols. The EETs play a well-documented role as endothelium-derived vasodilators in the systemic vasculature, but in the pulmonary circulation, they are generated in vascular smooth muscle cells and potentiate vasoconstriction. Preventing the breakdown of 11,12-EET by the inhibition or genetic deletion of the soluble epoxide hydrolase strongly augments the response to hypoxia. Mechanistically, 11,12-EET potentiates the contractile response by recruiting transient receptor potential C6 channels to caveolae. Indeed, neither 11,12-EET nor hypoxia is able to elicit pulmonary vasoconstriction in TRPC6 knockout mice. The cytochrome and soluble epoxide hydrolase enzymes are also implicated in the vascular remodeling associated with chronic hypoxia and pulmonary hypertension. Thus, targeting this pathway may be in an attractive new therapeutic approach to treat this incapacitating disease.
Loot
Annemarieke E
AE
Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany.
Fleming
Ingrid
I
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D050052:TRPC Cation Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000074287:TRPC6 Cation Channel
D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; C492146:Trpc6 protein, mouse; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D015126:8,11,14-Eicosatrienoic Acid