title: Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to the development of pulmonary arterial hypertension.
abstract: OBJECTIVE
  Pulmonary arterial hypertension [1] is a proliferative disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary artery smooth muscle cells (PASMCs). Reactive oxygen species (ROS) is implicated in the development of PAH and regulates the vascular tone and functions. However, which cellular signaling mechanisms are triggered by ROS in PAH is still unknown. Hence, here we wished to characterize the signaling mechanisms triggered by ROS.
  
  
  RESULTS
  By Western blots, we showed that increased intracellular ROS caused inhibition of the glycolytic pyruvate kinase M2 (PKM2) activity through promoting the phosphorylation of PKM2. Monocrotaline (MCT)-induced rats developed severe PAH and right ventricular hypertrophy, with a significant increase in the P-PKM2 and decrease in pyruvate kinase activity which could be attenuated with the treatments of PKM2 activators, FBP and l-serine. The antioxidant NAC, apocynin and MnTBAP had the similar protective effects in the development of PAH. In vitro assays confirmed that inhibition of PKM2 activity could modulate the flux of glycolytic intermediates in support of cell proliferation through the increased pentose phosphate pathway (PPP). Increased ROS and decreased PKM2 activity also promoted the Cav1.2 expression and intracellular calcium.
  
  
  CONCLUSIONS
  Our data provide new evidence that PKM2 makes a critical regulatory contribution to the PAHs for the first time. Decreased pyruvate kinase M2 activity confers additional advantages to rat PASMCs by allowing them to sustain anti-oxidant responses and thereby support cell survival in PAH. It may become a novel treatment strategy in PAH by using of PKM2 activators.
authors.affiliation: Molecular Pharmacology Laboratory, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Guo
authors.affiliation: Molecular Pharmacology Laboratory, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Junzhong
authors.initials: J
authors.lastname: Gu
authors.affiliation: Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproduction, Department of Urology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Aston Medical School, Aston University, Birmingham B4 7ET, UK.
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
authors.affiliation: Department of Cardiology, The 3(rd) Affiliated Hospital of Harbin Medical University, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150081, China.
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Molecular Pharmacology Laboratory, Institute of Molecular Medicine, Peking University, Beijing 100871, China. Electronic address: ycgu@pku.edu.cn.
authors.forename: Yuchun
authors.initials: Y
authors.lastname: Gu
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D016686:Monocrotaline; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009924:Organ Culture Techniques; D010427:Pentose Phosphate Pathway; D010766:Phosphorylation; D061251:Primary Cell Culture; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D011770:Pyruvate Kinase / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012694:Serine / Q000494:pharmacology
chemical_list: D000098:Acetophenones; C504728:Cacna1c protein, rat; D020746:Calcium Channels, L-Type; D008665:Metalloporphyrins; D017382:Reactive Oxygen Species; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D012694:Serine; D016686:Monocrotaline; C056165:acetovanillone; D011770:Pyruvate Kinase; D002118:Calcium; D000111:Acetylcysteine
keywords: Activators; PKM2; Pulmonary arterial hypertension; ROS