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Coronary heart disease is the leading cause of mortality globally. However, clinical translation of cardioprotective strategies against ischaemic reperfusion injury (IRI) has been disappointing. At The Hatter Cardiovascular Institute, the concept of the Reperfusion Injury Salvage Kinase (RISK) pathway was established, which includes PI3K activation of Akt.1 Our subsequent studies narrowed the target to the alpha isoform of PI3K, PI3Kα, which was shown to be both necessary and sufficient for cardioprotection by ischaemic preconditioning (IPC).2 A molecule that can bypass cell membrane to directly activate PI3Kα would be a promising novel therapy for IRI. As part of a larger collaboration, we recently developed the first allosteric activator of PI3Kα, UCL-TRO-1938 (or ‘1938’), and showed that it significantly reduced infarct size in an in-vivo IRI mouse model.3 We are now investigating the mechanisms of how PI3Kα activation exerts this protection. We hypothesized that 1938 activates PI3Kα signalling in cardiomyocytes, protecting them from injury.In a dose-response experiment in an isolated rat heart IRI model, 10μM 1938 was as protective as IPC, reducing the infarct size from 60 ± 4% to 41 ± 2% (N=8, P =0.01). In a dose-response experiment, in which H9C2 myoblast cells were treated with 500 μM H2O2 for 24 h, 1μM 1938 significantly reduced cell death from 30 ± 2% to 17 ± 1% (n=7, P=0.01). Western blot analysis confirmed that 1938 activates the PI3Kα/Akt pathway in both H9C2 and rat primary cardiomyocytes. After 15 min of treatment 1 μM 1938 significantly increased Akt phosphorylation by 2.0-fold vs. vehicle control (n=4, P=0.003).Future studies include investigating effect of 1938 in cardiomyocyte specific PI3Kα knockout mice to validate our hypothesis, and evaluate 1938’s effectiveness in models with co-morbidities. With comprehensive evaluation of this novel pharmacological approach, we hope to facilitate its successful clinical translation.References Yellon DM, Beikoghli Kalkhoran S, Davidson SM. The RISK pathway leading to mitochondria and cardioprotection: how everything started. Basic Res Cardiol. 2023 May 26;118(1):22. doi: 10.1007/s00395-023-00992-5. PMID: 37233787; PMCID: PMC10220132. Rossello X, Riquelme JA, He Z, Taferner S, Vanhaesebroeck B, Davidson SM, Yellon DM. The role of PI3Kα isoform in cardioprotection. Basic Res Cardiol. 2017 Oct 17;112(6):66. doi: 10.1007/s00395-017-0657-7. PMID: 29043508; PMCID: PMC5645445. Gong GQ, Bilanges B, Allsop B, et al. A small-molecule PI3Kα activator for cardioprotection and neuroregeneration. Nature. 2023 Jun;618(7963):159–168. doi: 10.1038/s41586-023-05972-2. Epub 2023 May 24. PMID: 37225977; PMCID: PMC7614683.