Abstract Body: Introduction: Myocardial infarction (MI) induces a cGAS-dependent type I interferon response at the infarct borderzone. Inhibiting this response genetically in mice reduces ventricular dilation and improves survival. A novel small molecule inhibitor of cGAS was developed and is in early clinical trials in humans. Whether pharmacologic inhibition of cGAS can achieve cardioprotection after MI is unknown.
Hypothesis: We hypothesize that pharmacologic treatment with Ventus’ proprietary mouse tool cGAS inhibitor (VEN-XXXX) can improve ventricular remodeling in mice after MI.
Methods: Adult C57BL/6 mice were treated with a small molecule cGAS inhibitor (VEN-XXXX) or vehicle (Veh) by twice daily oral gavage and subjected to MI. On day 4 after MI, when interferon responses are most prominent, we evaluated survival, performed echocardiography, and collected blood and cardiac tissue for cellular and biomolecular analysis.
Results: Survival of male mice treated with VEN-XXXX was 85% (18/21) while vehicle control was 69% (20/29). Echocardiography showed left ventricular inner dimension at end-diastole (LVIDD) was 4.44 +/- 0.38 mm in VEN-XXXX and 5.24 +/- 0.62 mm in vehicle, while at end-systole (LVIDS) it was 3.78 +/- 0.45 mm in VEN-XXXX and 4.66 +/- 0.64 mm in vehicle. Consistently, fractional shortening and ejection fraction were higher (14.69 +/- 3.64%) in VEN-XXXX compared with (11.18 +/- 3.28%) in vehicle. Sequencing-based spatial transcriptomics and chromogenic in situ hybridization for the interferon-stimulated gene Ifit1 and the border zone cardiomyocyte marker gene Nppa, were both reduced in VEN-XXXX-treated hearts compared to vehicle, demonstrating that cGAS inhibition attenuates borderzone ISG expression.
Conclusion: Short-term cGAS inhibition reduced type I IFN responses at the infarct borderzone, attenuated ventricular dilation, improved cardiac function, and exhibited increased survival. Together, this supports the therapeutic potential of cGAS inhibitors in the treatment of post-MI heart injury. Future work will investigate long-term outcomes.