Shiyu Hu1, Yang Gao1, Rifeng Gao2, Yiwen Wang1, Yanan Qu1, Ji'e Yang1, Xiang Wei2, Feng Zhang3, Junbo Ge4. 1. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China. 2. Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China. 3. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: zhang.feng@zs-hospital.sh.cn. 4. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: jbge@zs-hospital.sh.cn.
Abstract
BACKGROUND: During myocardial infarction (MI), the stimulation of the cGAS-STING-IRF3 pathway in infiltrated macrophages can induce the apoptosis of cardiomyocytes and the fibrosis of cardiac fibroblasts, while H-151 is reported as a selective STING inhibitor. We intended to use H-151 to alleviate MI injury. METHODS: Male C57BL/6J mice were subjected to induce MI, while H-151 (750 nmol) were used for treatment. Myocardial function was assessed through echocardiology and cardiac fibrosis was evaluated by Masson's Trichrome-staining. The stimulation of the STING pathway and the aggravation of inflammation was assessed by levels of protein and mRNA. BMDMs were stimulated by dsDNA extracted from the murine heart, while H-151 was used as treatment. After co-culturing adult cardiomyocytes and cardiac fibroblasts with supernatant of BMDMs, the apoptosis of adult cardiomyocytes and the fibrosis of cardiac fibroblasts was assessed. RESULTS: H-151 treatment showed significant function in preserving myocardial function and decreasing cardiac fibrosis 28 days after MI. H-151 treatment showed significant function in inhibiting the cGAS-STING-IRF3 pathway and inflammation, especially type I interferon response. H-151 could alleviate the type I interferon response in BMDMs elicited by cardiac dsDNA, and thus H-151 could attenuate the apoptosis of adult cardiomyocytes and fibrosis of cardiac fibroblasts after co-culturing them with the supernatant of BMDMs. CONCLUSIONS: H-151, a selective inhibitor of the cGAS-STING-IRF3 pathway, can preserve myocardial function and alleviate cardiac fibrosis after MI by inhibiting the type I interferon response in infiltrated macrophages triggered by cardiac dsDNA which increase the apoptosis of adult cardiomyocytes and fibrosis of cardiac fibroblasts.
BACKGROUND: During myocardial infarction (MI), the stimulation of the cGAS-STING-IRF3 pathway in infiltrated macrophages can induce the apoptosis of cardiomyocytes and the fibrosis of cardiac fibroblasts, while H-151 is reported as a selective STING inhibitor. We intended to use H-151 to alleviate MI injury. METHODS: Male C57BL/6J mice were subjected to induce MI, while H-151 (750 nmol) were used for treatment. Myocardial function was assessed through echocardiology and cardiac fibrosis was evaluated by Masson's Trichrome-staining. The stimulation of the STING pathway and the aggravation of inflammation was assessed by levels of protein and mRNA. BMDMs were stimulated by dsDNA extracted from the murine heart, while H-151 was used as treatment. After co-culturing adult cardiomyocytes and cardiac fibroblasts with supernatant of BMDMs, the apoptosis of adult cardiomyocytes and the fibrosis of cardiac fibroblasts was assessed. RESULTS: H-151 treatment showed significant function in preserving myocardial function and decreasing cardiac fibrosis 28 days after MI. H-151 treatment showed significant function in inhibiting the cGAS-STING-IRF3 pathway and inflammation, especially type I interferon response. H-151 could alleviate the type I interferon response in BMDMs elicited by cardiac dsDNA, and thus H-151 could attenuate the apoptosis of adult cardiomyocytes and fibrosis of cardiac fibroblasts after co-culturing them with the supernatant of BMDMs. CONCLUSIONS: H-151, a selective inhibitor of the cGAS-STING-IRF3 pathway, can preserve myocardial function and alleviate cardiac fibrosis after MI by inhibiting the type I interferon response in infiltrated macrophages triggered by cardiac dsDNA which increase the apoptosis of adult cardiomyocytes and fibrosis of cardiac fibroblasts.
Authors: Yao Du; Hui Zhang; Xiaoyan Nie; Yajun Qi; Shi Shi; Yingying Han; Wenchen Zhou; Chaoyong He; Lintao Wang Journal: Front Cardiovasc Med Date: 2022-08-22