p22phox promotes Ang-II-induced vascular smooth muscle cell phenotypic switch by regulating KLF4 expression

Yixin Tang; Qin Huang; Chaoyan Liu; Hongji Ou; Dan Huang; Fengling Peng; Changhui Liu; Zhongcheng Mo

doi:10.1016/j.bbrc.2019.04.128

p22phox promotes Ang-II-induced vascular smooth muscle cell phenotypic switch by regulating KLF4 expression

Biochem Biophys Res Commun. 2019 Jun 18;514(1):280-286. doi: 10.1016/j.bbrc.2019.04.128. Epub 2019 Apr 26.

Authors

Yixin Tang¹, Qin Huang², Chaoyan Liu¹, Hongji Ou¹, Dan Huang¹, Fengling Peng³, Changhui Liu⁴, Zhongcheng Mo⁵

Affiliations

¹ Department of Cardiovascular Medicine, First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China.
² Clinical Anatomy & Reproductive Medicine Application Institute, Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, 421001, China.
³ Department of Neurology, First Affiliated Hospital of University of South China, Hengyang, 421001, China.
⁴ Department of Cardiovascular Medicine, First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China. Electronic address: nhfylch@sina.com.
⁵ Clinical Anatomy & Reproductive Medicine Application Institute, Department of Histology and Embryology, Hengyang Medical School, University of South China, Hengyang, 421001, China. Electronic address: zhchmo@hotmail.com.

PMID: 31030942
DOI: 10.1016/j.bbrc.2019.04.128

Abstract

NADPH oxidase (Nox) is the main source of reactive oxygen species in vascular diseases, which have been implicated in promoting VSMCs phenotypic switch. P22phox, the indispensable component of the complex Nox, is required for their activity and stability. Krüppel-like factor 4 (KLF4) is an important transcriptional regulator of VSMCs phenotypic switch. Both KLF4 and p22phox are involved in the proliferation, migration and differentiation of VSMC. This study aims to determine whether and how p22phox regulates KLF4 expression in phenotypic switching of VSMCs. In cultured primary rat VSMCs, we noticed that the expression of P22phox was significantly increased in combination with VSMCs phenotypic switch and up-regulated KLF4 expression in Ang-II-treated cells. Ang-II-induced VSMC dedifferentiation, proliferation, migration, KLF4 expression, H₂O₂ production and the phosphorylation of AKT, ERK1/2 were all inhibited by knockdown of P22phox. Furthermore, H₂O₂ treatment effectively enhanced the phosphorylation of AKT, ERK1/2 and the expression of KLF4, whereas LY294002 (a specific inhibitor of PI3K), U0126 (a specific inhibitor of ERK1/2) significantly attenuated the H2O2-induced up-regulation of KLF4. In conclusion, these results demonstrated that p22phox promotes Ang-II-induced VSMC phenotypic switch via the H₂O₂-ERK1/2/AKT-KLF4 signaling pathway.

Keywords: Ang-II; KLF4; Reactive oxygen species; VSMC phenotypic switch; p22phox.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin II / metabolism*
Angiotensin II / pharmacology
Animals
Cell Differentiation
Cell Movement
Cell Proliferation
Cells, Cultured
Hydrogen Peroxide / metabolism
Hydrogen Peroxide / pharmacology
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors / metabolism*
MAP Kinase Signaling System / drug effects
Male
Muscle, Smooth, Vascular / cytology*
Muscle, Smooth, Vascular / drug effects
Muscle, Smooth, Vascular / physiology
NADPH Oxidases / genetics
NADPH Oxidases / metabolism*
Phenotype
Proto-Oncogene Proteins c-akt / metabolism
Rats, Sprague-Dawley

Substances

Klf4 protein, rat
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
Angiotensin II
Hydrogen Peroxide
NADPH Oxidases
Cyba protein, rat
Proto-Oncogene Proteins c-akt