LAUSR

Acute myocardial infarction (MI) is a major cause of morbidity and mortality. Massive cell death leads to inflammation, a necessary evil for wound healing, but also “evil” or harmful due to infarct expansion and adverse remodeling. Also, studies in experimental models have demonstrated the potential cytoprotective effects of nitric oxide (NO) supplemented at the time of reperfusion. In these experiments, we investigated whether RRx-001, a NO donor only under hypoxia and an NLRP3 inflammasome inhibitor, in a Phase 3 trial (REPLATINUM; NCT03699956) for the treatment of cancer was protective after MI. Methods: Male Sprague-Dawley rats (n=8/group) subjected to coronary ligation and reperfusion were randomized to receive either no treatment (sham), vehicle control, or 5mg/kg intravenous RRx-001 at 1-hour post-infarction. We assessed structural and functional cardiac remodeling, infarct expansion, fibrosis, cardiomyocyte hypertrophy, and the expression of inflammatory genes. Results: Treatment with RRx-001 after reperfused MI decreased infarct expansion and scarring, increased left ventricular systolic function to levels approaching normal values, and reduced myocardial hypertrophy. No hypotensive effects were observed. Postinfarction was associated with the activation of NF-κB and NLRP3 inflammasome components and increased the protein and expression of IL-1β. Compared with vehicle, infarcted rats treated with RRx-001 significantly attenuated myocardial messenger RNA and protein levels of NF-κB, NLRP3 inflammasome, mature caspase-1, and IL-1β. Significance: This is the first report that RRx-001 reduces infarct size. It provides proof of principle for administering RRx-001 against ischemia/reperfusion injury. RRx-001 increases local NO levels under hypoxia without requiring the continuous intravenous infusion of NO donors and without altering systemic hemodynamics. It can potentially improve wound healing responses and pathological remodeling, thereby attenuating the development of ischemic heart failure. Commercial and private foundation grants. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.