The selective STING inhibitor H-151 preserves myocardial function and ameliorates cardiac fibrosis in murine myocardial infarction.

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.

• Authors: Shiyu Hu, Yang Gao, Rifeng Gao, Yiwen Wang, Yanan Qu, Ji'e Yang, Xiang Wei, Feng Zhang, Junbo Ge
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 107 Pg. 108658 (Jun 2022) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 35278833 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Interferon Type I
• Nucleotidyltransferases

Topics

• Animals
• Fibrosis
• Inflammation (metabolism)
• Interferon Type I (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction (metabolism)
• Myocardium (pathology)
• Myocytes, Cardiac (metabolism)
• Nucleotidyltransferases (metabolism)