M-type pyruvate kinase 2 (PKM2) tetramerization alleviates the progression of right ventricle failure by regulating oxidative stress and mitochondrial dynamics.
M-type pyruvate kinase 2 (PKM2) tetramerization alleviates the progression of right ventricle failure by regulating oxidative stress and mitochondrial dynamics.
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DOI：
10.1186/s12967-023-04780-6
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发表时间：
2023-12-07
影响因子：
7.4
通讯作者：
Wang E
中科院分区：
文献类型：
--
作者：
Guo L;Wang L;Qin G;Zhang J;Peng J;Li L;Chen X;Wang D;Qiu J;Wang E
右心室衰竭（RVF）是一种进行性心脏病，尚未在分子水平上得到充分了解。 M 型丙酮酸激酶 2 (PKM2) 四聚化可缓解心力衰竭，但详细的分子机制仍不清楚。我们观察了右心衰竭和体外心肌细胞肥大进展过程中 PKM2 四聚化水平的变化，并探讨了 PKM2 四聚化改变与心肌细胞氧化还原稳态失衡之间的因果关系及其潜在机制。最终，我们的目标是提出治疗裂谷热的合理干预策略。我们通过腹腔注射野百合碱 (MCT) 在 Sprague Dawley (SD) 大鼠中建立 RVF。采用经胸超声心动图联合右心导管检查评估大鼠肺动脉压和右心功能。 TEPP-46 在体内和体外均用于促进 PKM2 四聚化。我们观察到氧化应激和线粒体紊乱与 RVF 大鼠右心室组织细胞凋亡增加有关。定量蛋白质组学显示 PKM2 在 RVF 期间表达上调，并与心功能呈负相关。促进 PKM2 四聚化促进线粒体网络形成并减轻心肌细胞肥大期间的氧化应激和细胞凋亡。此外，增强 PKM2 四聚体形成可以改善心脏线粒体形态，减轻氧化应激并减轻心力衰竭。 PKM2四聚化的破坏通过诱导线粒体断裂、ROS积累而导致RVF，最终促进心肌细胞凋亡的进展。促进 PKM2 四聚化具有作为 RVF 一种有前途的治疗方法的潜力。在线版本包含可在 10.1186/s12967-023-04780-6 获取的补充材料。
Right ventricle failure (RVF) is a progressive heart disease that has yet to be fully understood at the molecular level. Elevated M-type pyruvate kinase 2 (PKM2) tetramerization alleviates heart failure, but detailed molecular mechanisms remain unclear. We observed changes in PKM2 tetramerization levels during the progression of right heart failure and in vitro cardiomyocyte hypertrophy and explored the causal relationship between altered PKM2 tetramerization and the imbalance of redox homeostasis in cardiomyocytes, as well as its underlying mechanisms. Ultimately, our goal was to propose rational intervention strategies for the treatment of RVF. We established RVF in Sprague Dawley (SD) rats by intraperitoneal injection of monocrotaline (MCT). The pulmonary artery pressure and right heart function of rats were assessed using transthoracic echocardiography combined with right heart catheterization. TEPP-46 was used both in vivo and in vitro to promote PKM2 tetramerization. We observed that oxidative stress and mitochondrial disorganization were associated with increased apoptosis in the right ventricular tissue of RVF rats. Quantitative proteomics revealed that PKM2 was upregulated during RVF and negatively correlated with the cardiac function. Facilitating PKM2 tetramerization promoted mitochondrial network formation and alleviated oxidative stress and apoptosis during cardiomyocyte hypertrophy. Moreover, enhancing PKM2 tetramer formation improved cardiac mitochondrial morphology, mitigated oxidative stress and alleviated heart failure. Disruption of PKM2 tetramerization contributed to RVF by inducing mitochondrial fragmentation, accumulating ROS, and finally promoted the progression of cardiomyocyte apoptosis. Facilitating PKM2 tetramerization holds potential as a promising therapeutic approach for RVF. The online version contains supplementary material available at 10.1186/s12967-023-04780-6.
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影响因子：
20.1
作者：
Carlson CR;Aronsen JM;Bergan-Dahl A;Moutty MC;Lunde M;Lunde PK;Jarstadmarken H;Wanichawan P;Pereira L;Kolstad TRS;Dalhus B;Subramanian H;Hille S;Christensen G;Müller OJ;Nikolaev V;Bers DM;Sjaastad I;Shen X;Louch WE;Klussmann E;Sejersted OM
通讯作者：
Sejersted OM
DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
Cantley LC
影响因子：
11.2
作者：
Apostolidi M;Vathiotis IA;Muthusamy V;Gaule P;Gassaway BM;Rimm DL;Rinehart J
通讯作者：
Rinehart J
影响因子：
13.6
作者：
通讯作者：
--
线粒体 PKM2 通过稳定 Bcl2 来调节氧化应激诱导的细胞凋亡。
影响因子：
44.1
作者：
Liang J;Cao R;Wang X;Zhang Y;Wang P;Gao H;Li C;Yang F;Zeng R;Wei P;Li D;Li W;Yang W
通讯作者：
Yang W