Herting Julius R, Berg Anna M, Hadova Katarina, Heinick Alexander, König Simone, Kuhlmann Michael, Müller Frank U, Kirchhefer Uwe
Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität Münster, Domagkstr. 12, 48149 Münster, Germany.
Interdisziplinäres Zentrum für Klinische Forschung, Integrierte Funktionelle Genomik, Westfälische Wilhelms-Universität Münster, Röntgenstraße 21, 48149 Münster, Germany.
J Mol Cell Cardiol Plus. 2022 Dec 27;3:100030. doi: 10.1016/j.jmccpl.2022.100030. eCollection 2023 Mar.
Protein phosphatase 2A (PP2A) plays a central role in myocardial ischemia-reperfusion (I/R) injury. Several studies showed a detrimental function of PP2A by using either overexpression models of the catalytic subunit (PP2Ac) or exogenous inhibitors of PP2Ac. However, all of these approaches underestimate the contribution of regulatory B subunits in modulating the PP2A holoenzyme. To better understand the influence of B subunits on a "controlled" regulation of PP2A, we tested a mouse model overexpressing PP2A-B56α (TG) in the heart under the conditions of I/R in comparison to wild-type littermates (WT). Contractility was increased after reperfusion in isolated TG hearts that were initially subjected to a 20-min no-flow ischemia. This was associated with lower phosphorylation levels of myosin-binding protein C and the ryanodine receptor 2 in TG compared to WT. The application of okadaic acid abolished the contractile and biochemical effects in TG hearts. Moreover, reperfusion resulted in the detection of higher PP2A-B56α levels in mitochondrial preparations of TG hearts. The phosphorylation of ERK1 was increased in the early reperfusion phase in TG compared to WT hearts corresponding to a transient attenuation of PP2A activity. Ischemia led to a prolonged contracture time in TG hearts and a lower acidification in isolated TG cardiomyocytes. The formation of interstitial fibrosis by transient ligation of the left anterior descending (LAD) artery was reduced in TG compared to WT hearts. Taken together, these findings indicate that overexpression of PP2A-B56α is protective against I/R injury and that B56α merits further investigation as a potential therapeutic target.
蛋白磷酸酶2A（PP2A）在心肌缺血再灌注（I/R）损伤中起核心作用。多项研究通过使用催化亚基（PP2Ac）的过表达模型或PP2Ac的外源性抑制剂，显示了PP2A的有害功能。然而，所有这些方法都低估了调节性B亚基在调节PP2A全酶中的作用。为了更好地理解B亚基对PP2A“受控”调节的影响，我们测试了一种在心脏中过表达PP2A-B56α（TG）的小鼠模型，与野生型同窝小鼠（WT）相比，在I/R条件下进行研究。最初经历20分钟无血流缺血的离体TG心脏在再灌注后收缩性增强。与WT相比，TG中肌球蛋白结合蛋白C和兰尼碱受体2的磷酸化水平较低。应用冈田酸消除了TG心脏中的收缩和生化效应。此外，再灌注导致在TG心脏的线粒体制剂中检测到更高水平的PP2A-B56α。与WT心脏相比，TG在再灌注早期阶段ERK1的磷酸化增加，这与PP2A活性的短暂减弱相对应。缺血导致TG心脏的挛缩时间延长，离体TG心肌细胞的酸化程度降低。与WT心脏相比，TG中通过短暂结扎左前降支（LAD）动脉形成的间质纤维化减少。综上所述，这些发现表明PP2A-B56α的过表达对I/R损伤具有保护作用，并且B56α作为潜在治疗靶点值得进一步研究。
