RNA sequencing was used to profile circRNA expression in adult mouse cardiomyocytes that were isolated from mice with or without exercise training. Exercise-induced circRNA circUtrn was significantly increased in swimming-trained adult mouse cardiomyocytes. In vivo, circUtrn was found to be required for exercise-induced physiological cardiac hypertrophy. circUtrn inhibition abolished the protective effects of exercise on myocardial ischaemia-reperfusion remodelling. circUtrn overexpression prevented myocardial ischaemia-reperfusion-induced acute injury and pathological cardiac remodelling. In vitro, overexpression of circUtrn promoted H9 human embryonic stem cell-induced cardiomyocyte growth and survival via protein phosphatase 5 (PP5). Mechanistically, circUtrn directly bound to PP5 and regulated the stability of PP5 in a ubiquitin-proteasome-dependent manner. Hypoxia-inducible factor 1α-dependent splicing factor SF3B1 acted as an upstream regulator of circUtrn in cardiomyocytes.
The circRNA circUtrn is upregulated upon exercise training in the heart. Overexpression of circUtrn can prevent myocardial I/R-induced injury and pathological cardiac remodelling.
结果:RNA测序用于分析成年小鼠心肌细胞中的circRNA表达,这些心肌细胞是从有或没有运动训练的小鼠中分离的。在游泳训练的成年小鼠心肌细胞中,运动诱导的circRNA-cirUtrn显着增加。在体内,发现circUtrn是运动引起的生理性心脏肥大所必需的。CircUtrn抑制消除了运动对心肌缺血/再灌注重塑的保护作用。CircUtrn过表达可预防心肌缺血/再灌注引起的急性损伤和病理性心脏重塑。体外,circUtrn的过表达通过蛋白磷酸酶PP5促进H9人胚胎干细胞诱导的心肌细胞生长和存活。机械上,circUtrn直接结合PP5并以泛素-蛋白酶体依赖性方式调节PP5的稳定性。缺氧诱导因子1α依赖性剪接因子SF3B1在心肌细胞中充当cirUtrn的上游调节因子。
结论:circRNACircUtrn在心脏运动训练后上调。circUtrn的过表达可以预防I/R引起的心肌损伤和病理性心脏重塑。
■CircRNAcirUtrn是运动诱发的生理性心脏肥大发展所必需的。CircUtrn抑制消除了运动对I/R重塑的保护作用。此外,circUtrn过表达可预防心肌I/R诱导的急性损伤和病理性心脏重塑。我们的发现表明,circUtrn升高及其对I/R损伤的保护作用可能在I/R损伤和病理性心脏重塑中具有治疗前景。