Stable EET urea agonist and soluble epoxide hydrolase inhibitor regulate rat pulmonary arteries through TRPCs. Hypertens Res 2011 May;34(5):630-9
Date
02/11/2011Pubmed ID
21307870Pubmed Central ID
PMC4548928DOI
10.1038/hr.2011.5Scopus ID
2-s2.0-79955600318 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
Epoxyeicosatrienoic acids (EETs), cytochrome P450-derived metabolites of arachidonic acid, have been reported to increase intracellular calcium concentration in aortic vascular smooth muscle cells (SMCs). As EETs are labile, we synthesized a new stable urea EET analog with agonist and soluble epoxide hydrolase (sEH) inhibitor properties. We refer to this analog, 12-(3-hexylureido)dodec-8-enoic acid, as 8-HUDE. Measuring tension of vascular rings, intracellular calcium signaling by confocal laser scanning microscopy and gene expression by reverse-transcription-PCR and western blots, we examined the effects of 8-HUDE on pulmonary vascular tone and calcium signaling in rat pulmonary artery (PA) SMCs (PASMCs). 8-HUDE increased the tension of rat PAs to 145% baseline, whereas it had no effect on the tension of mesenteric arteries (MAs). The 8-HUDE-induced increase in vascular tone was abolished by removal of extracellular Ca(2+) or by pretreatment with either La(3+) or SKF96365, which are inhibitors of canonical transient receptor potential channels (TRPCs). Furthermore, 8-HUDE-evoked increases in [Ca(2+)](i) in PASMCs could be blunted by inhibition of TRPC with SKF96365, removal of extracellular calcium or depletion of intracellular calcium stores with caffeine, cyclopiazonic acid or 2-aminoethoxydiphenyl borate, but not by the voltage-activated calcium channel blocker nifedipine. In addition to immediate effects on calcium signaling, 8-HUDE upregulated the expression of TRPC1 and TRPC6 at both mRNA and protein levels in rat PASMCs, whereas it suppressed the expression of sEH. Our observations suggest that 8-HUDE increases PA vascular tone through increased release of calcium from intracellular stores, enhanced [Ca(2+)](i) influx in PASMCs through store-operated Ca(2+) channels and modulated the expression of TRPC and sEH proteins in a proconstrictive manner.
Author List
Liu Y, Wang R, Li J, Rao J, Li W, Falck JR, Manthati VL, Medhora M, Jacobs ER, Zhu DMESH terms used to index this publication - Major topics in bold
AnimalsBoron Compounds
Caffeine
Calcium Channel Blockers
Calcium Signaling
Cells, Cultured
Enzyme Inhibitors
Epoxide Hydrolases
Fatty Acids, Monounsaturated
Female
Imidazoles
Indoles
Lanthanum
Male
Mesenteric Arteries
Muscle, Smooth, Vascular
Nifedipine
Pulmonary Artery
Rats
Rats, Wistar
Transient Receptor Potential Channels
