Interferon regulatory factor 7 inhibits rat vascular smooth muscle cell proliferation and inflammation in monocrotaline-induced pulmonary hypertension

Autor: Yan Deng, Fen Wang, Sheng-lan Guo, Ying-chuan Zhou, Jia-quan Li, Shan-shan Xie, Qian Wang, Bin Wei
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
Vascular smooth muscle
Heart Ventricles
Hypertension
Pulmonary
Interferon Regulatory Factor-7
Survivin
Myocytes
Smooth Muscle
Receptor for Advanced Glycation End Products
Apoptosis
Core Binding Factor Alpha 1 Subunit
Inflammation
Vascular Remodeling
030226 pharmacology & pharmacy
Muscle
Smooth
Vascular
General Biochemistry
Genetics and Molecular Biology
Proinflammatory cytokine
Rats
Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Proliferating Cell Nuclear Antigen
medicine
Animals
Cyclin D1
General Pharmacology
Toxicology and Pharmaceutics
Lung
Cells
Cultured
Cell Proliferation
bcl-2-Associated X Protein
Activating Transcription Factor 3
Monocrotaline
Caspase 3
Chemistry
Hemodynamics
General Medicine
Dependovirus
medicine.disease
Pulmonary hypertension
Up-Regulation
030104 developmental biology
Cancer research
IRF7
Tumor necrosis factor alpha
medicine.symptom
Signal Transduction
Zdroj: Life Sciences. 264:118709
ISSN: 0024-3205
DOI: 10.1016/j.lfs.2020.118709
Popis: Aims Although interferon regulatory factor 7 (IRF7) has known roles in regulating the inflammatory response, vascular smooth muscle cell proliferation, and apoptosis, its role in the pathogenesis of pulmonary hypertension (PH) is unclear. We hypothesized that IRF7 overexpression could inhibit pulmonary vascular remodeling and slow the progression of PH. Main methods IRF7 mRNA and protein levels in the lung samples and pulmonary artery smooth muscle cells (PASMCs) isolated from monocrotaline (MCT)-induced PH rats were assessed. We evaluated the effects of IRF7 on inflammation, proliferation, and apoptosis using an in vivo MCT-induced PH rat model and in vitro methods. Key findings We noted decreased IRF7 mRNA and protein levels in the pulmonary vasculature of MCT-induced PH rats. IRF7 upregulation attenuated pulmonary vascular remodeling, decreased the pulmonary artery systolic pressure, and improved the right ventricular (RV) structure and function. Our findings suggest that nuclear factor kappa-Bp65 (NF-κBp65) deactivation could confer pulmonary vasculature protection, reduce proinflammatory cytokine (tumor necrosis factor-α, interleukin 6) release, and decrease PASMC proliferation and resistance to apoptosis via deactivating transcription factor 3 (ATF3) signaling. ATF3 deactivation induced the downregulation of the proliferation-dependent genes proliferating cell nuclear antigen (PCNA), cyclin D1, and survivin, coupled with increased levels of B cell lymphoma-2-associated X protein (Bax)/B cell lymphoma-2 (Bcl2) ratio, and cleaved caspase-3 in PASMCs. Significance Our findings showed that IRF7 downregulation could initiate inflammation via NF-κBp65 signaling, causing PASMC proliferation via ATF3 signaling pathway activation. Therefore, IRF7 could be a potential molecular target for PH therapy.
Databáze: OpenAIRE
Externí odkaz: