An activator of PI3Kα restores cardioprotection from ischaemia/reperfusion injury in mice with coronary atherosclerosis or insulin resistance

Abstract

Background In patients with coronary artery disease (CAD), morbidity and mortality from myocardial infarction remain high. Cardioprotective strategies such as Remote Ischaemic Conditioning (RIC) are highly effective in animal models but have disappointed in large clinical trials. One explanation may be that ischaemia and reperfusion (I/R) experiments are typically conducted in mice that lack CAD. Unlike most mouse models, double-knockout Scarb1;Ldlr (DKO) mice do develop CAD when fed a high-fat diet (HFD). The aim of this study was therefore to use these mice to investigate cardioprotection in the setting of CAD. We hypothesized that RIC, which requires cell-surface receptor signalling, would be ineffective in these mice; but that UCL-TRO-1938, a PI3Kalpha activator that bypasses cell-surface receptors, would be cardioprotective. Methods and results After 6-weeks HFD, DKO mice, but not WT or Ldlr KO mice, developed CAD as determined by histology. Anaesthetized mice were subject to 30-min coronary ischaemia and 2-h reperfusion. In line with our hypothesis, RIC did reduce infarct size in WT and Ldlr KO mice, but did not reduce infarct size in DKO mice subject to I/R. We sought to understand the effects of CAD in DKO hearts that might impair RIC, using RNAseq, immunostaining and Western blot analysis. RNAseq revealed significantly altered gene expression in DKO hearts compared to WT and Ldlr KO hearts, primarily in inflammatory pathways; in particular the IL-17 pathway. Coronary endothelial cells were activated, as shown by ICAM-1 expression in DKO but not Ldlr KO or WT. In contrast to RIC, treatment with UCL-TRO-1938 was cardioprotective in DKO mice. Conclusions The DKO mouse may be a more clinically translatable mouse model of I/R and cardioprotection. Furthermore, UCL-TRO-1938 is a promising cardioprotective drug as it remains effective in a mouse model with CAD.