1. Academic Validation
  2. Platelet-Derived TGF (Transforming Growth Factor)-β1 Enhances the Aerobic Glycolysis of Pulmonary Arterial Smooth Muscle Cells by PKM2 (Pyruvate Kinase Muscle Isoform 2) Upregulation

Platelet-Derived TGF (Transforming Growth Factor)-β1 Enhances the Aerobic Glycolysis of Pulmonary Arterial Smooth Muscle Cells by PKM2 (Pyruvate Kinase Muscle Isoform 2) Upregulation

  • Hypertension. 2022 May;79(5):932-945. doi: 10.1161/HYPERTENSIONAHA.121.18684.
Ying Zhu 1 2 Dan Shu 1 2 3 Xue Gong 1 2 Meng Lu 1 2 Qinyu Feng 1 2 4 Xiang-Bin Zeng 1 2 Han Zhang 1 2 5 6 Jiahui Gao 1 2 Ya-Wei Guo 1 2 Luman Liu 1 2 Rong Ma 1 2 Liping Zhu 1 2 5 6 Qinghua Hu 1 2 5 6 Zhang-Yin Ming 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (Y.Z., D.S., X.G., M.L., X.-B.Z., J.G., Y.W.G., L.L., R.M., Z.-Y.M.).
  • 2 The Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China (Y.Z., D.S., X.G., M.L., X.-B.Z., J.G., Y.W.G., L.L., R.M., Z.-Y.M.).
  • 3 Department of Pharmacy, School of Medicine, Wuhan University of Science and Technology, Wuhan, China (D.S.).
  • 4 Department of Gastroenterology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (Q.F.).
  • 5 Department of Pathophysiology, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan China (H.Z., L.Z., Q.H.).
  • 6 Key Laboratory of Pulmonary Diseases of Ministry of Health, Wuhan China (H.Z., L.Z., Q.H.).
Abstract

Background: Metabolic reprogramming is a hallmark of pulmonary arterial hypertension. Platelet activation has been implicated in pulmonary arterial hypertension (PAH), whereas the role of platelet in the pathogenesis of PAH remains unclear.

Methods: First, we explored the platelet function of semaxanib' a inhibitor of VEGF receptor (SU5416)/hypoxia mice and monocrotaline-injected rats PAH model. Then we investigated pulmonary arterial smooth muscle cell aerobic glycolysis after being treated with platelet supernatant. TGF (transforming growth factor)-βRI, Pyruvate Kinase muscle 2, and other antagonists were applied to identify the underlying mechanism. In addition, platelet-specific deletion TGF-β1 mice were exposed to chronic hypoxia and SU5416. Cardiopulmonary hemodynamics, vascular remodeling, and aerobic glycolysis of pulmonary arterial smooth muscle cell were determined.

Results: Here, we demonstrate that platelet-released TGF-β1 enhances the aerobic glycolysis of pulmonary arterial smooth muscle cells after platelet activation via increasing Pyruvate Kinase muscle 2 expression. Mechanistically, platelet-derived TGF-β1 regulate spyruvate kinase muscle 2 expression through mTOR (mammalian target of rapamycin)/c-Myc/PTBP-1(polypyrimidine tract binding protein 1)/hnRNPA-1(heterogeneous nuclear ribonucleoprotein A1) pathway. Platelet TGF-β1 deficiency mice are significantly protected from SU5416 plus chronic hypoxia-induced PAH, including attenuated increases in right ventricular systolic pressure and less pulmonary vascular remodeling. Also, in Pf4cre+ Tgfb1fl/fl mice, pulmonary arterial smooth muscle cells showed lower glycolysis capacity and their Pyruvate Kinase muscle 2 expression decreased.

Conclusions: Our data demonstrate that TGF-β1 released by platelet contributes to the pathogenesis of PAH and further highlights the role of platelet in PAH.

Keywords

glycolysis; hypoxia; platelet activation; pulmonary arterial hypertension; transforming growth factor.

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