1-Methyl-2-undecyl-4(1H)-quinolone, a derivative of quinolone alkaloid evocarpine, attenuates high phosphate-induced calcification of human aortic valve interstitial cells by inhibiting phosphate cotransporter PiT-1

Kazuhiko Seya, Ken Ichi Furukawa, Mari Chiyoya, Zaiqiang Yu, Haruhisa Kikuchi, Kazuyuki Daitoku, Shigeru Motomura, Manabu Murakami, Yoshiteru Oshima, Ikuo Fukuda

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10 Citations (Scopus)

Abstract

An abnormally high serum phosphate level induces calcific aortic stenosis (CAS), which is characterized by ectopic valve calcification and stenosis of the orifice area. Inhibition of ectopic calcification is a critical function of any internal medical therapy for CAS disease. The aim of the present study was to investigate the inhibitory effects of several derivatives of evocarpine, methanolic extracts from the fruits of Evodia rutaecarpa Bentham (Japanese name: Go-Shu-Yu) on the high phosphate-induced calcification of human aortic valve interstitial cells (HAVICs) obtained from patients with CAS. High phosphate (3.2 mM) concentrations significantly increased the calcification of HAVICs after 7 days of culture. This calcification was completely inhibited in the presence of sodium phosphonoformate (PFA), a selective inhibitor of the type III sodium-dependent phosphate cotransporter (PiT-1). PiT-1 contributes to phosphate uptake, resulting in calcification. 1-Methyl-2-undecyl-4(1H)-quinolone (MUQ; 30-300 nM), but not evocarpine or its derivatives dihydroevocarpine and 1-methyl-2-nonyl-4(1H)-quinolone, inhibited the high phosphate-induced HAVICs calcification in a concentration-dependent manner. Although all of the evocarpine derivatives attenuated alkaline phosphatase activity, only MUQ also decreased PiT-1 gene expression with cellular PiT-1 protein diminution. These results suggest that MUQ mitigated high phosphate-induced HAVICs calcification by inhibiting PiT-1 gene expression.

Original languageEnglish
Pages (from-to)51-57
Number of pages7
JournalJournal of Pharmacological Sciences
Volume131
Issue number1
DOIs
Publication statusPublished - 2016 May 1

Keywords

  • 1-Methyl-2-undecyl-4(1H)-quinolone
  • Aortic valve interstitial cells
  • Calcification
  • High phosphate
  • PiT-1

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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