PKM2调控线粒体动力学对肺动脉高压血管重构的影响及机制

Pulmonary hypertension (PAH) is a fatal disease, characterized by pulmonary vascular remodeling, Metabolic disorders are one of the important pathogenesis of pulmonary hypertension. Our previous metabomonic study demonstrated that metabolic shift from oxidative phosphorylation to glycolysis in the sera of monocrotaline-induced PAH rats. Concordantly, pyruvate kinase M2 (PKM2), a rate-limiting enzyme that catalyzes the last step in glycolysis, was increased in pulmonary artery in PAH rats. It is well known that PKM2 is involved in the regulation of mitochondrial dynamics and plays an pivotal role in aerobic glycolysis. As a result, we hypothesized that regulation of mitochondrial dynamics by upregulation of PKM2 caused metabolic dysfunction, abnormal proliferation of pulmonary artery smooth muscle cells and pulmonary vascular remodeling in the pathogenesis of PAH. The aim of this study was to investigate regulatory mechanisms of PKM2 expression and activity, role of PKM2 in regulation of mitochondrial fusion and fission, the effect of imbalance of mitochondrial homeostasis on metabolism and cell proliferation in PKM2 knockout mice and pulmonary arterial smooth musclce cells, and explore the possibility of PKM2 as a therapeutic target of PAH.

肺动脉高压（PAH）是以肺血管重构为主要病理变化的致死性疾病，代谢异常是重要发病机制之一。我们前期代谢组学研究发现，野百合碱诱导的PAH大鼠葡萄糖代谢模式由线粒体氧化磷酸化向糖酵解转化，肺动脉中参与糖酵解最后一步的关键限速酶M2型丙酮酸激酶（PKM2）表达也增加。也有研究发现PAH中线粒体片段化增加，线粒体动力学稳态失衡。已知PKM2参与线粒体动力学的调控，并在糖酵解中起重要作用。据此我们假设：在PAH发病过程中，PKM2表达上调，参与线粒体动力学调控，导致线粒体片段化和代谢异常，促进肺动脉平滑肌细胞（PASMC）异常增殖和血管重构。本项目拟以PKM2基因敲除的小鼠和PASMC为研究对象，研究PAH发病过程中PKM2表达上调和活性调节机制、PKM2对线粒体融合和分裂的调控，及其对糖代谢和PASMC增殖的影响，探索以PKM2作为PAH治疗靶点的可能性。

肺动脉高压（PAH）是以肺血管重构为主要病理变化的致死性疾病。糖酵解关键限速酶M2型丙酮酸激酶（PKM2）在PAH发病过程中发挥重要作用。也有研究发现线粒体动力学稳态失衡参与PAH的发生发展。在该项目的支持下，我们通过转录组测序发现在野百合碱诱导的PAH动物模型肺组织中，参与糖酵解多个关键酶表达上调。其中PKM2表达上调，促进Drp1的磷酸化，促进肺动脉平滑肌细胞（PASMC）异常增殖和血管重构。PKM2的抑制剂shikonin可抑制PAH PASMC中Drp1的磷酸化，抑制细胞增殖。本项目探索了PKM2调控细胞增殖的机制，明确PKM2可通过磷酸化Drp1，影响PAH中PASMC的增殖。

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