PMID- 27718461
OWN - NLM
STAT- MEDLINE
DCOM- 20170203
LR  - 20170921
IS  - 1950-6007 (Electronic)
IS  - 0753-3322 (Linking)
VI  - 84
DP  - 2016 Dec
TI  - Iptakalim induces mitochondria-dependent apoptosis in hypoxic rat pulmonary 
      arterial smooth muscle cells.
PG  - 773-779
LID - S0753-3322(16)30737-5 [pii]
LID - 10.1016/j.biopha.2016.09.031 [doi]
AB  - OBJECTIVES: Pulmonary vascular medial hypertrophy in hypoxic pulmonary arterial 
      hypertension (HPH) is caused in part by decreased apoptosis in pulmonary artery 
      smooth muscle cells (PASMCs). Iptakalim (Ipt), an ATP sensitive potassium channel 
      opener, ameliorates HPH in animal models. Here we investigated the effects of Ipt 
      on proliferation and apoptosis of hypoxic rat PASMCs, and to determine the 
      possible underlying mechanisms. METHODS: Primary rat PASMCs were isolated and 
      cultured. PASMCs were cultured for 24h in normoxia or hypoxia (5% O(2)) 
      conditions with and without Ipt. Cell proliferation and cycle were determined by 
      MTT assay and flow cytometry, respectively. Mitochondrial membrane potential 
      (Deltaym) was detected by fluorescence microscope Western blot assays were used to 
      examine the expression of cyclin D, CDK4, endothelin-1 (ET-1), hypoxia-inducible 
      factor-1 (HIF-1), platelet-derived growth factor-BB (PDGF-BB), Bax, Bcl-2, 
      cytochrome c (Cyt c), caspase-9, and caspase-3 in PASMCs. RESULTS: We found that 
      hypoxia significantly stimulated proliferation and rendered resistance to 
      apoptosis in PASMCs. Ipt suppressed proliferation and induced cell cycle arrest 
      in hypoxia PASMCs. Ipt decreased the expression of cyclin D, CDK4, HIF-1, ET-1, 
      and PDGF-BB in hypoxia PASMCs. It reversed the depolarization of Deltapsim in hypoxia 
      PASMCs too. Ipt significantly upregulated Bax expression and downregulated Bcl-2 
      expression, and promoted the release of Cyt c from mitochondria to cytoplasm in 
      hypoxia PASMCs. Furthermore, Ipt significantly activated the caspase cascades 
      evidenced by increased expression of caspase-9 and caspase-3 in hypoxia PASMCs. 
      CONCLUSIONS: Ipt could inhibit cell proliferation and induce apoptosis associated 
      with cell cycle arrest, decreased ET-1, HIF-1, cyclin D, CDK4, PDGF-BB and Deltapsim, 
      increased Bax/Bcl-2 ratio, enhanced Cyt c release, and activation of caspases in 
      PASMCs under hypoxia status. Our data indicated that Ipt could be a therapeutic 
      candidate for treatment of HPH.
CI  - Copyright (c) 2016 Elsevier Masson SAS. All rights reserved.
FAU - Xu, Qi
AU  - Xu Q
AD  - Department of Respiratory Medicine, The first Affiliated Hospital of Nanjing 
      Medical University Nanjing 210029, China.
FAU - Wu, Xiang
AU  - Wu X
AD  - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, 
      China.
FAU - Li, Yu
AU  - Li Y
AD  - School of Basic Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, 
      China.
FAU - Kong, Hui
AU  - Kong H
AD  - Department of Respiratory Medicine, The first Affiliated Hospital of Nanjing 
      Medical University Nanjing 210029, China.
FAU - Jin, Yu
AU  - Jin Y
AD  - Department of Respiratory Medicine, The first Affiliated Hospital of Nanjing 
      Medical University Nanjing 210029, China.
FAU - Xie, Weiping
AU  - Xie W
AD  - Department of Respiratory Medicine, The first Affiliated Hospital of Nanjing 
      Medical University Nanjing 210029, China.
FAU - Wang, Hong
AU  - Wang H
AD  - Department of Respiratory Medicine, The first Affiliated Hospital of Nanjing 
      Medical University Nanjing 210029, China. Electronic address: 1319420655@qq.com.
LA  - eng
PT  - Journal Article
DEP - 20161005
PL  - France
TA  - Biomed Pharmacother
JT  - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
JID - 8213295
RN  - 0 (N-(1-methylethyl)-1,1,2-trimethylpropylamine)
RN  - 0 (Propylamines)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects/physiology
MH  - Cell Hypoxia/drug effects/physiology
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - Male
MH  - Mitochondria/*drug effects/metabolism
MH  - Muscle, Smooth, Vascular/*drug effects/metabolism
MH  - Myocytes, Smooth Muscle/*drug effects/metabolism
MH  - Propylamines/*pharmacology
MH  - Pulmonary Artery/*drug effects/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
OTO - NOTNLM
OT  - Apoptosis
OT  - Caspase
OT  - Cytochrome c
OT  - Hypoxic pulmonary hypertension
OT  - Iptakalim
OT  - Pulmonary artery smooth muscle cell
EDAT- 2016/10/09 06:00
MHDA- 2017/02/06 06:00
CRDT- 2016/10/09 06:00
PHST- 2016/05/26 00:00 [received]
PHST- 2016/08/17 00:00 [revised]
PHST- 2016/09/09 00:00 [accepted]
PHST- 2016/10/09 06:00 [pubmed]
PHST- 2017/02/06 06:00 [medline]
PHST- 2016/10/09 06:00 [entrez]
AID - S0753-3322(16)30737-5 [pii]
AID - 10.1016/j.biopha.2016.09.031 [doi]
PST - ppublish
SO  - Biomed Pharmacother. 2016 Dec;84:773-779. doi: 10.1016/j.biopha.2016.09.031. Epub 
      2016 Oct 5.