Golforoush Pelin, Sulaiman Elias, He David, Yellon Derek M, Davidson Sean M
The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK.
Cardiovasc Res. 2025 Sep 29;121(11):1722-1733. doi: 10.1093/cvr/cvaf111.
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-mutant SR-BIΔCT/ΔCT;Ldlr KO 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 phosphatidylinositol 3-kinase alpha (PI3Kα) activator that bypasses cell-surface receptors, would be cardioprotective.
After 6-week HFD, double-mutant mice, but not wild-type (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 reduced infarct size in WT and Ldlr KO mice, but did not reduce infarct size in double-mutant mice subject to I/R. We sought to understand the effects of CAD in double-mutant mouse hearts that might impair RIC, using RNA-sequencing (RNA-seq), immunostaining, and Western blot analysis. RNA-seq revealed significantly altered gene expression in double-mutant hearts compared with WT and Ldlr KO hearts, primarily in inflammatory pathways; in particular the interleukin-17 pathway. Coronary endothelial cells were activated, as shown by ICAM-1 expression in double-mutant but not Ldlr KO or WT. In contrast to RIC, treatment with UCL-TRO-1938 was cardioprotective in double-mutant mice.
The double-mutant SR-BIΔCT/ΔCT;Ldlr KO mouse strain 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.
在冠状动脉疾病（CAD）患者中，心肌梗死导致的发病率和死亡率仍然很高。远程缺血预处理（RIC）等心脏保护策略在动物模型中非常有效，但在大型临床试验中却令人失望。一种解释可能是，缺血再灌注（I/R）实验通常在没有CAD的小鼠中进行。与大多数小鼠模型不同，双突变SR-BIΔCT/ΔCT;Ldlr KO小鼠在喂食高脂饮食（HFD）时确实会患上CAD。因此，本研究的目的是使用这些小鼠来研究CAD情况下的心脏保护作用。我们假设，需要细胞表面受体信号传导的RIC在这些小鼠中无效；但绕过细胞表面受体的磷脂酰肌醇3-激酶α（PI3Kα）激活剂UCL-TRO-1938具有心脏保护作用。
在6周的HFD喂养后，通过组织学检查确定双突变小鼠而非野生型（WT）或Ldlr KO小鼠患上了CAD。对麻醉的小鼠进行30分钟的冠状动脉缺血和2小时的再灌注。与我们的假设一致，RIC减少了WT和Ldlr KO小鼠的梗死面积，但没有减少接受I/R的双突变小鼠的梗死面积。我们试图通过RNA测序（RNA-seq）、免疫染色和蛋白质印迹分析来了解CAD在双突变小鼠心脏中可能损害RIC的影响。RNA-seq显示，与WT和Ldlr KO心脏相比，双突变心脏中的基因表达有显著改变，主要在炎症途径中；特别是白细胞介素-17途径。如双突变小鼠而非Ldlr KO或WT小鼠中ICAM-1的表达所示，冠状动脉内皮细胞被激活。与RIC相反，用UCL-TRO-1938治疗对双突变小鼠具有心脏保护作用。
双突变SR-BIΔCT/ΔCT;Ldlr KO小鼠品系可能是一种更具临床可转化性的I/R和心脏保护小鼠模型。此外，UCL-TRO-1938是一种有前景的心脏保护药物，因为它在患有CAD的小鼠模型中仍然有效。
