OMT-28 is a metabolically robust small molecule developed to mimic the structure and function of omega-3 epoxyeicosanoids. However, it remained unknown to what extent OMT-28 also shares the cardio-protective and anti-inflammatory properties of its natural counterparts. To address this question, we analyzed the ability of OMT-28 to ameliorate hypoxia/reoxygenation (HR)-injury and lipopolysaccharide (LPS)-induced endotoxemia in cultured cardiomyocytes. Moreover, we investigated the potential of OMT-28 to limit functional damage and inflammasome activation in isolated perfused mouse hearts subjected to ischemia/reperfusion (IR) injury. In the HR model, OMT-28 (1 μM) treatment largely preserved cell viability (about 75 vs. 40 % with vehicle) and mitochondrial function as indicated by the maintenance of NAD+/NADH-, ADP/ATP- and respiratory control ratios. Moreover, OMT-28 blocked the HR-induced production of mitochondrial reactive oxygen species. Pharmacological inhibition experiments suggested that Gαi, PI3K, PPARα, and Sirt1 are essential components of the OMT-28 mediated pro-survival pathway. Counteracting inflammatory injury of cardiomyocytes, OMT-28 (1 μM) reduced LPS-induced increases in TNFα protein (by about 85 % vs vehicle) and NF-κB DNA binding (by about 70 % vs. vehicle). In the ex vivo model, OMT-28 improved post-IR myocardial function recovery to reach about 40 % of the baseline value compared to less than 20 % with vehicle. Furthermore, OMT-28 (1 μM) limited IR-induced NLRP3 inflammasome activation similarly like a direct NLRP3 inhibitor (MCC950). Overall, this study demonstrates that OMT-28 possesses potent cardio-protective and anti-inflammatory properties supporting the hypothesis that extending the bioavailability of omega-3 epoxyeicosanoids may improve their prospects as therapeutic agents.

OMT-28

Cardioprotection

Analog

17,18-EEQ

Oxylipin

Eicosanoid

NADH-oxidoreductase

Succinate dehydrogenase

Epoxydocosapentaenoic acid

Monocyte chemoattractant protein 1

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

Nuclear Factor Kappa B

Neonatal Rat Cardiomyocytes

Polyunsaturated fatty acid

Sarcolemmal ATP sensitive potassium channel

Transforming Growth Factor Beta

Tumor Necrosis Factor

© 2024 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.