Stable EET urea agonist and soluble epoxide hydrolase inhibitor regulate rat pulmonary arteries through TRPCs

Yun Liu, Ruifang Wang, Jing Li, Jingjing Rao, Weiyang Li, J R Falck, Vijay L. Manthati, Meetha Medhora, Elizabeth R. Jacobs, Daling Zhu

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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 Ca2+ 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 Ca2+ 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 Ca2+ i influx in PASMCs through store-operated Ca2+ channels and modulated the expression of TRPC and sEH proteins in a proconstrictive manner.

Original languageEnglish (US)
Pages (from-to)630-639
Number of pages10
JournalHypertension Research
Volume34
Issue number5
DOIs
StatePublished - May 1 2011

Keywords

  • 12-(3-hexylureido)dodec-8-enoic acid
  • 8-HUDE
  • canonical transient receptor potential channel (TRPC)
  • epoxyeicosatrienoic acids (EETs)
  • pulmonary arteries
  • store-operated Ca channels (SOCCs)

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Liu, Y., Wang, R., Li, J., Rao, J., Li, W., Falck, J. R., Manthati, V. L., Medhora, M., Jacobs, E. R., & Zhu, D. (2011). Stable EET urea agonist and soluble epoxide hydrolase inhibitor regulate rat pulmonary arteries through TRPCs. Hypertension Research, 34(5), 630-639. https://doi.org/10.1038/hr.2011.5