Interferon regulatory factor 7 (IRF7) plays a key role to regulate an inflammatory response, inhibits vascular smooth cell proliferation and promotes apoptosis. But its role in pulmonary hypertension (PH) pathology is essentially unknown. We hypothesized that downregulation IRF7 promotes pulmonary vascular remodeling and that overexpression of IRF7 could slow the progression of PH.
mRNA, and protein levels of IRF7 were assessed in the lung samples and isolated pulmonary artery smooth muscle cells (PASMCs) from MCT-induced PH in rats. The preventive effects of IRF7 up-regulation were tested in the MCT induced PH rat. The effects of IRF7 on inflammation, proliferation, apoptosis, and AFT3 signaling were tested in cultured rat PASMCs.
mRNA and protein levels of IRF7 were decreased in vivo and in vitro in the pulmonary vascular from MCT induced PH rats. Genetically up-regulation IRF7 with adeno-associated virus attenuated pulmonary vascular remodeling, resulted in decreasing pulmonary artery systolic pressure and improving the right ventricular structure and function. The pulmonary vascular protective effect worked by reducing pro-inflammatory cytokine levels (TNF-α, IL-6), as well as abrogating PASMCS proliferation and apoptosis resistance via ATF3 signaling. ATF3 activation augmented the proliferation-dependent genes (PCNA1, Cyclin D1) and anti-apoptotic regulators (Capase-3 and Bax) in PASMCs.
Our data provide evidence that down-regulation of IRF7 cold initiate inflammation response, cause PASMCs proliferation and apoptosis resistance via activation of ATF3 signaling pathway. Activation of IRF7 could be a potential therapeutic target for treating PH.
Copyright © 2018. Published by Elsevier Inc.