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International Journal Of Bilogical Sciences

.: Home > International Journal Of Bilogical Sciences > 2015 > Volume 11 Number 6 > Zen-Kong Dai1, Yu-Wei Liu2, Jong-Hau Hsu1, Jwu-Lai Yeh2, Ing-Jun Chen2, Jiunn-Ren Wu1, , Bin-Nan Wu2

The Xanthine Derivative KMUP-1 Attenuates Serotonin-Induced Vasoconstriction and K+-Channel Inhibitory Activity via the PKC Pathway in Pulmonary Arteries

Zen-Kong Dai1, Yu-Wei Liu2, Jong-Hau Hsu1, Jwu-Lai Yeh2, Ing-Jun Chen2, Jiunn-Ren Wu1, , Bin-Nan Wu2
1. Department of Pediatrics, Division of Pediatric Pulmonology and Cardiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 2. Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan  Corresponding authors: Jiunn-Ren Wu M.D., Ph.D., Department of Pediatrics, Division of Pediatric Pulmonology and Cardiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Fax: 886-7-3213931; E-mail: jirewu@kmu.edu.tw. Bin-Nan Wu Ph.D., Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan. Fax: 886-7-3234686; E-mail: binnan@kmu.edu.tw
Abstract :

Serotonin (5-hydroxytryptamine, 5-HT) is a potent pulmonary vasoconstrictor that promotes pulmonary artery smooth muscle cell (PASMC) proliferation. 5-HT-induced K+ channel inhibition increases [Ca2+]i in PASMCs, which is a major trigger for pulmonary vasoconstriction and development of pulmonary arterial hypertension (PAH). This study investigated whether KMUP-1 reduces pulmonary vasoconstriction in isolated pulmonary arteries (PAs) and attenuates 5-HT-inhibited K+ channel activities in PASMCs. In endothelium-denuded PA rings, KMUP-1 (1 μM) dose-dependently reduced 5-HT (100 μM) mediated contractile responses. Responses to KMUP-1 were reversed by K+ channel inhibitors (TEA, 10 mM, 4-aminopyridine, 5 mM, and paxilline, 10 μM). In primary PASMCs, KMUP-1 also dose-dependently restored 5-HT-inhibited voltage-gated K+-channel (Kv1.5 and Kv2.1) and large-conductance Ca2+-activated K+-channel (BKCa) proteins, as confirmed by immunofluorescent staining. Furthermore, 5-HT (10 μM)-inhibited Kv1.5 protein was unaffected by the PKA inhibitor KT5720 (1 μM) and the PKC activator PMA (1 μM), but these effects were reversed by KMUP-1 (1 μM), 8-Br-cAMP (100 μM), chelerythrine (1 μM), and KMUP-1 combined with a PKA/PKC activator or inhibitor. Notably, KMUP-1 reversed 5-HT-inhibited Kv1.5 protein and this response was significantly attenuated by co-incubation with the PKC activator PMA, suggesting that 5-HT-mediated PKC signaling can be modulated by KMUP-1. In conclusion, KMUP-1 ameliorates 5-HT-induced vasoconstriction and K+-channel inhibition through the PKC pathway, which could be valuable to prevent the development of PAH.

Keywords :
Serotonin, pulmonary vasoconstriction, K+-channel inhibition, Kv1.5 protein, PKC signaling, pulmonary artery smooth muscle cells

Date Deposited : 23 Feb 2016 13:13

Last Modified : 23 Feb 2016 13:13

Official URL: http://www.ijbs.com/v11i6

Volume 11, Number 6, - 2015 , ISSN 1449-2288

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