Open AccessRadiation‐induced C‐reactive protein triggers apoptosis of vascular smooth muscle cells through ROS interfering with the STAT3/Ref‐1 complex
Author(s) -
Ryu JeWon,
Jung InHye,
Park EunYoung,
Kim KangHyun,
Kim Kyunggon,
Yeom Jeonghun,
Jung Jinhong,
Lee Sangwook
Publication year - 2022
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.17233
Subject(s) - vascular smooth muscle , apoptosis , stat3 , inflammation , nadph oxidase , cancer research , chemistry , microbiology and biotechnology , signal transduction , reactive oxygen species , biology , immunology , endocrinology , biochemistry , smooth muscle
Damage to normal tissue can occur over a long period after cancer radiotherapy. Free radical by radiation can initiate or accelerate chronic inflammation, which can lead to atherosclerosis. However, the underlying mechanisms remain unclear. Vascular smooth muscle cells (VSMCs) proliferate in response to JAK/STAT3 signalling. C‐reactive protein (CRP) can induce VSMCs apoptosis via triggering NADPH oxidase (NOX). Apoptotic VSMCs promote instability and inflammation of atherosclerotic lesions. Herein, we identified a VSMCs that switched from proliferation to apoptosis through was enhanced by radiation‐induced CRP. NOX inhibition using lentiviral sh‐p22 phox prevented apoptosis upon radiation‐induced CRP. CRP overexpression reduced the amount of STAT3/Ref‐1 complex, decreased JAK/STAT phosphorylation and formed a new complex of Ref‐1/CRP in VSMC. Apoptosis of VSMCs was further increased by CRP co‐overexpressed with Ref‐1. Functional inhibition of NOX or p53 also prevented apoptotic activity of the CRP‐Ref‐1 complex. Immunofluorescence showed co‐localization of CRP, Ref‐1 and p53 with α‐actin‐positive VSMC in human atherosclerotic plaques. In conclusion, radiation‐induced CRP increased the VSMCs apoptosis through Ref‐1, which dissociated the STAT3/Ref‐1 complex, interfered with JAK/STAT3 activity, and interacted with CRP‐Ref‐1, thus resulting in transcription‐independent cell death via p53. Targeting CRP as a vascular side effect of radiotherapy could be exploited to improve curability.