PMID- 31829402
OWN - NLM
STAT- MEDLINE
DCOM- 20201016
LR  - 20211204
IS  - 1573-4935 (Electronic)
IS  - 0144-8463 (Print)
IS  - 0144-8463 (Linking)
VI  - 39
IP  - 12
DP  - 2019 Dec 20
TI  - Pioglitazone protects blood vessels through inhibition of the apelin signaling 
      pathway by promoting KLF4 expression in rat models of T2DM.
LID - 10.1042/BSR20190317 [doi]
LID - BSR20190317
AB  - Apelin, identified as the endogenous ligand of APJ, exerts various cardiovascular 
      effects. However, the molecular mechanism underlying the regulation of apelin 
      expression in vascular cells is poorly described. Pioglitazone (PIO) and 
      Kruppel-like factor 4 (KLF4) exhibit specific biological functions on vascular 
      physiology and pathophysiology by regulating differentiation- and 
      proliferation-related genes. The present study aimed to investigate the roles of 
      PIO and KLF4 in the transcriptional regulation of apelin in a high-fat 
      diet/streptozotocin rat model of diabetes and in PIO-stimulated vascular smooth 
      muscle cells (VSMCs). Immunohistochemistry, qRT-PCR, and Western blotting assays 
      revealed that the aorta of the Type 2 diabetes mellitus (T2DM) rat models had a 
      high expression of apelin, PIO could decrease the expression of apelin in the 
      PIO-treated rats. In vitro, Western blotting assays and immunofluorescent 
      staining results showed that the basal expression of apelin was decreased but 
      that of KLF4 was increased when VSMCs were stimulated by PIO treatment. 
      Luciferase and chromatin immunoprecipitation assay results suggested that KLF4 
      bound to the GKLF-binding site of the apelin promoter and negatively regulated 
      the transcription activity of apelin in VSMCs under PIO stimulation. Furthermore, 
      qRT-PCR and Western blotting assay results showed that the overexpression of KLF4 
      markedly decreased the basal expression of apelin, but the knockdown of KLF4 
      restored the PIO-induced expression of apelin. In conclusion, PIO inhibited the 
      expression of apelin in T2DM rat models to prevent diabetic macroangiopathy, and 
      negatively regulated the gene transcription of apelin by promoting transcription 
      of KLF4 in the apelin promoter.
CI  - (c) 2019 The Author(s).
FAU - Wang, Ying
AU  - Wang Y
AD  - The First Affiliated Hospital, Henan University, Kaifeng, Henan 475004, China.
AD  - The Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery of 
      School of Basic Medicine, Henan University, Kaifeng, Henan 475004, China.
FAU - Zhang, Ruonan
AU  - Zhang R
AD  - School of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang 
      050017, China.
FAU - Shen, Hailin
AU  - Shen H
AD  - The Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery of 
      School of Basic Medicine, Henan University, Kaifeng, Henan 475004, China.
FAU - Kong, Jing
AU  - Kong J
AD  - The Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery of 
      School of Basic Medicine, Henan University, Kaifeng, Henan 475004, China.
FAU - Lv, Xinrui
AU  - Lv X
AD  - The Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery of 
      School of Basic Medicine, Henan University, Kaifeng, Henan 475004, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biosci Rep
JT  - Bioscience reports
JID - 8102797
RN  - 0 (Apelin)
RN  - 0 (Apln protein, rat)
RN  - 0 (KLF4 protein, human)
RN  - 0 (Klf4 protein, rat)
RN  - 0 (Kruppel-Like Factor 4)
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - X4OV71U42S (Pioglitazone)
SB  - IM
MH  - Animals
MH  - Apelin/*genetics
MH  - Blood Vessels/drug effects
MH  - Diabetes Mellitus, Type 2/*drug therapy/genetics/pathology
MH  - Disease Models, Animal
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Kruppel-Like Factor 4
MH  - Kruppel-Like Transcription Factors/*genetics
MH  - Pioglitazone/*pharmacology
MH  - Rats
MH  - Signal Transduction/drug effects
PMC - PMC6928522
OTO - NOTNLM
OT  - Apelin
OT  - KLF4
OT  - Macroangiopathy
OT  - Pioglitazone
OT  - STZ
OT  - VSMCs
COIS- The authors declare that there are no competing interests associated with the 
      manuscript.
EDAT- 2019/12/13 06:00
MHDA- 2020/10/21 06:00
PMCR- 2019/12/24
CRDT- 2019/12/13 06:00
PHST- 2019/02/05 00:00 [received]
PHST- 2019/11/16 00:00 [revised]
PHST- 2019/12/02 00:00 [accepted]
PHST- 2019/12/13 06:00 [pubmed]
PHST- 2020/10/21 06:00 [medline]
PHST- 2019/12/13 06:00 [entrez]
PHST- 2019/12/24 00:00 [pmc-release]
AID - 221480 [pii]
AID - BSR20190317 [pii]
AID - 10.1042/BSR20190317 [doi]
PST - ppublish
SO  - Biosci Rep. 2019 Dec 20;39(12):BSR20190317. doi: 10.1042/BSR20190317.