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| Item Type: | Article |
|---|---|
| Title: | Cardioprotective properties of OMT-28, a synthetic analog of omega-3 epoxyeicosanoids |
| Creators Name: | Kranrod, J., Konkel, A., Valencia, R., Darwesh, A., Fischer, R., Schunck, W.H. and Seubert, J.M. |
| Abstract: | 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. |
| Keywords: | OMT-28, Cardioprotection, Analog, 17,18-EEQ, Oxylipin, Eicosanoid, Animals, Mice |
| Source: | Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Publisher: | Elsevier |
| Volume: | 300 |
| Number: | 6 |
| Page Range: | 107372 |
| Date: | June 2024 |
| Official Publication: | https://doi.org/10.1016/j.jbc.2024.107372 |
| PubMed: | View item in PubMed |
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