Inhibition of heterogeneous nuclear ribonucleoproteins A1 and oxidative stress reduces glycolysis via pyruvate kinase M2 in chronic thromboembolic pulmonary hypertension.
Lianhua Liu, Wenyi Pang, Jixiang Liu, Shiqing Xu, Zhu Zhang, Risheng Hao, Jun Wan, Wanmu Xie, Xincao Tao, Peiran Yang, Lan Zhao, Zhenguo Zhai, Chen Wang
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引用次数: 0
Abstract
Background and objective: Chronic thromboembolic pulmonary hypertension (CTEPH) is a lethal complication of pulmonary embolism involving pulmonary artery occlusion and microvascular disease. The glucose metabolism and reactive oxygen species (ROS) production may be perturbed in CTEPH, but the precise mechanisms are unclear. This study investigated glucose metabolism in CTEPH employing pulmonary endarterectomy (PEA)-derived pulmonary artery smooth muscle cells (PASMCs) and characterized the roles of pyruvate kinase M2 (PKM2) and its regulation by heterogeneous nuclear ribonucleoproteins A1 (hnRNPA1) and ROS in CTEPH.
Methods: PEA tissues and blood samples of CTEPH patients were collected to study the levels of PKM2. Primary PASMCs were isolated from PEA tissues. We used small interfering RNAs to knock down PKM2 and hnRNPAI, and applied antioxidant N-acetylcysteine (NAC) and mito-TEMPO to reduce ROS production. The expression of glucometabolic genes, ROS production, glycolysis rate and proliferative and migratory activities were analyzed in PEA-derived PASMCs.
Results: PKM2 levels in serum and PEA tissues of CTEPH patients were higher than that of the healthy controls. Compared to the control PASMCs, PEA-derived PASMCs showed increased PKM2 expression and ROS production. The rates of glycolysis, proliferation and migration were increased in PEA-PASMCs and could be mitigated by PKM2 downregulation through hnRNPA1 or ROS inhibition.
Conclusions: Increased glycolysis and PKM2 expression were found in PEA-PASMCs. Inhibition of hnRNPA1 or ROS corrected the aberrant glycolysis, cell proliferation and migration by downregulating PKM2. Regulation of the hnRNPA1/PKM2 axis represents a potential therapeutic target for the treatment of CTEPH.
期刊介绍：
A peer-reviewed journal, Alternatives explores the possibilities of new forms of political practice and identity under increasingly global conditions. Specifically, the editors focus on the changing relationships between local political practices and identities and emerging forms of global economy, culture, and polity. Published in association with the Center for the Study of Developing Societies (India).
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