title: 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.
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.
authors.affiliation: Department of Pharmacology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Seya
authors.affiliation: Department of Pharmacology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan. Electronic address: furukawa@hirosaki-u.ac.jp.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Furukawa
authors.affiliation: Department of Pharmacology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; Department of Thoracic and Cardiovascular Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Chiyoya
authors.affiliation: Department of Pharmacology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; Department of Thoracic and Cardiovascular Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Zaiqiang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Daitoku
authors.affiliation: Department of Pharmacology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Motomura
authors.affiliation: Department of Pharmacology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Oshima
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Fukuda
mesh_terms: D000368:Aged; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D001021:Aortic Valve / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000378:metabolism*; D002114:Calcinosis / Q000378:metabolism*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D010710:Phosphates; D015363:Quinolones / Q000494:pharmacology*; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C000618672:1-methyl-2-undecyl-4(1H)-quinolone; D010710:Phosphates; D015363:Quinolones; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D000469:Alkaline Phosphatase
keywords: 1-Methyl-2-undecyl-4(1H)-quinolone; Aortic valve interstitial cells; Calcification; High phosphate; PiT-1