Small molecule STING inhibition improves myocardial infarction remodeling

Journal article

Aims: Myocardial infarction (MI) is a major global cause of death. Massive cell death leads to inflammation, which is necessary for ensuing wound healing. Extensive inflammation, however, promotes infarct expansion and adverse remodeling. The DNA sensing receptor cyclic GMP-AMP synthase and its downstream signaling effector stimulator of interferon genes (cGAS-STING) is central in innate immune reactions in infections or autoimmunity. Cytosolic double-strand DNA activates the pathway and down-stream inflammatory responses. Recent papers demonstrated that this pathway is also active following MI and that its genetic targeting improves outcome. Thus, we investigated if pharmacologic pathway inhibition is protective after MI in order to test its translational potential.

Main methods: We investigated novel and selective small-molecule STING inhibitors that inhibit STING palmitoylation and multimerization and thereby downstream pathway activation in a preclinical murine MI model. We assessed structural and functional cardiac remodeling, infarct expansion and fibrosis, as well as cardiomyocyte hypertrophy and the expression of inflammatory genes.

Key findings: Pharmacologic STING inhibition did not reduce mortality due to myocardial rupture in non-reperfused MI. Infarct size at day one was comparable. However, three weeks of pharmacologic STING inhibition after reperfused MI decreased infarct expansion and scarring, increased left ventricular systolic function to levels approaching normal values, and reduced myocardial hypertrophy.

Significance: Selective small-molecule STING inhibition after myocardial infarction has the potential to improve wound healing responses and pathological remodeling and thereby attenuate the development of ischemic heart failure.

Authors: Rech, L; Abdellatif, M; Pöttler, M; Stangl, V; Mabotuwana, N

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Life Sciences
• Volume: 291
• Article number: 120263
• Publication date: 2021-12-28
• Acceptance date: 2021-12-18
• DOI: 10.1016/j.lfs.2021.120263
• ISSN: 0024-3205
• Pmid: 34971697
• Language: English
• Keywords: animals; systole; biological sciences; development of treatments and therapeutic interventions; inflammation; good health and well being; biochemistry and cell biology; left ventricular function; signal transduction; ventricular remodeling; myocardial infarction; cardiovascular; membrane proteins; inbred C57BL mice; coronary heart disease; heart failure; male; biomedical and clinical sciences; pharmaceuticals; lipoylation; heart; nucleotidyltransferases; mice; FFR; heart disease; genetics