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PFKFB3-Mediated Endothelial Glycolysis Promotes Pulmonary Hypertension

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PFKFB3-Mediated Endothelial Glycolysis Promotes Pulmonary Hypertension PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension Yapeng Caoa,b,c,d,e, Xiaoyu Zhanga,b,c,d,e, Lina Wanga,b,c,d,e, Qiuhua Yanga,b,c,d,e, Qian Maa,b,c,d,e, Jiean Xua,b,c,d,e, Jingjing Wanga,b,c, Laszlo Kovacsf, Ramon J. Ayong, Zhiping Liua,b,c,d,e, Min Zhanga,b,c, Yaqi Zhoua,b,c, Xianqiu Zenga,b,c, Yiming Xud,e,h, Yong Wangd,e,i, David J. Fultond,e, Neal L. Weintraubd,e, Rudolf Lucasd,e, Zheng Dongj, Jason X.-J. Yuang, Jennifer C. Sullivank, Louise Meadowsf, Scott A. Barmanf, Chaodong Wul, Junmin Quana,b,c, Mei Honga,b,c,1,2, Yunchao Suf,1,2, and Yuqing Huod,e,1,2 aDrug Discovery Center, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, 518055 Shenzhen, China; bState Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, 518055 Shenzhen, China; cKey Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, 518055 Shenzhen, China; dVascular Biology Center, Augusta University, Augusta, GA 30912; eDepartment of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912; fDepartment of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912; gDivision of Translational and Regenerative Medicine, Department of Medicine, University of Arizona, Tucson, AZ 85721-0202; hSchool of Basic Medical Sciences, The 6th Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, 511436 Guangzhou, China; iCollege of Basic Medicine, Chengdu University of Traditional Chinese Medicine, 610075 Chengdu, China; jDepartment of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912; kDepartment of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912; and lDepartment of Nutrition and Food Science, Texas A&M University, College Station, TX 77840 Edited by Matthew G. Vander Heiden, Koch Institute at Massachusetts Institute of Technology, and accepted by Editorial Board Member Barbara B. Kahn May 29, 2019 (received for review December 20, 2018) Increased glycolysis in the lung vasculature has been connected to the development of PH. Positron emission tomography (PET) scans 18 the development of pulmonary hypertension (PH). We therefore with [ F]-fluoro-deoxy-D-glucose (FDG) performed in rodents investigated whether glycolytic regulator 6-phosphofructo-2-kinase/ with experimental PH and patients with idiopathic pulmonary fructose-2, 6-bisphosphatase (PFKFB3)-mediated endothelial glycol- arterial hypertension (IPAH) show significantly higher glucose – ysis plays a critical role in the development of PH. Heterozygous uptake in the lungs (5 8), suggesting increased glycolytic activity in CELL BIOLOGY global deficiency of Pfkfb3 protected mice from developing hypoxia- PH lungs. Furthermore, it has been found that many cell types in induced PH, and administration of the PFKFB3 inhibitor 3PO almost the PH lung, including endothelial cells from patients with IPAH completely prevented PH in rats treated with Sugen 5416/hypoxia, (5, 7, 9), PASMCs from rodents with experimental PH and hu- indicating a causative role of PFKFB3 in the development of PH. mans with IPAH (7, 10), as well as vascular fibroblasts isolated Immunostaining of lung sections and Western blot with isolated from IPAH patients and calves with severe hypoxia-induced pul- lung endothelial cells showed a dramatic increase in PFKFB3 expres- monary hypertension (8), rely heavily on glycolysis for increased sion and activity in pulmonary endothelial cells of rodents and hu- growth. Although aerobic glycolysis is an inefficient way to gen- mans with PH. We generated mice that were constitutively or erate adenosine 5′-triphosphate (ATP), it nevertheless provides inducibly deficient in endothelial Pfkfb3 and found that these mice macromolecules, lipids, and many other molecules that support were incapable of developing PH or showed slowed PH progression. the rapid growth of proliferating cells (11). The up-regulation of Compared with control mice, endothelial Pfkfb3-knockout mice exhibited less severity of vascular smooth muscle cell proliferation, Significance endothelial inflammation, and leukocyte recruitment in the lungs. In the absence of PFKFB3, lung endothelial cells from rodents and hu- Lung endothelial cells express high levels of glucose metabolic mans with PH produced lower levels of growth factors (such as enzymes, such as PFKFB3, and consequently produce large PDGFB and FGF2) and proinflammatory factors (such as CXCL12 amounts of glucose metabolites. These metabolites are able to and IL1β). This is mechanistically linked to decreased levels of HIF2A stabilize the cell signaling molecule HIF2A, similar to that which in lung ECs following PFKFB3 knockdown. Taken together, these occurs under hypoxic conditions. This stabilization of HIF2A by results suggest that targeting PFKFB3 is a promising strategy for glucose metabolites in lung endothelial cells stimulates pro- the treatment of PH. duction of growth and inflammatory factors, thereby enhanc- ing proliferation and inflammation of the pulmonary vessels endothelial cells | glycolysis | pulmonary hypertension and exacerbating pulmonary hypertension (PH). In this study, blockade of endothelial PFKFB3 inhibits PH development in ulmonary hypertension (PH) is a severe lung disease char- rodent models, suggesting that targeting glucose metabolic Pacterized by the remodeling of small pulmonary vessels, leading enzymes is a promising strategy for the treatment of PH. to a progressive increase in pulmonary vascular resistance and ul- timately culminating in right ventricular failure and death. The Author contributions: Y.C. and Y.H. designed research; Y.C., X.Z., L.W., Q.Y., Q.M., J.X., J.W., L.K., R.J.A., Z.L., and Y.X. performed research; Y.C., M.Z., Y.Z., X.Z., Y.W., R.L., Z.D., cardinal pathological changes of PH include increased proliferation J.X.-J.Y., J.C.S., L.M., S.A.B., C.W., and Y.H. contributed new reagents/analytic tools; Y.C., and resistance to apoptosis of pulmonary arterial endothelial and X.Z., L.W., Q.Y., Q.M., J.X., D.J.F., N.L.W., J.Q., M.H., Y.S., and Y.H. analyzed data; and Y.C., smooth muscle cells (PAECs and PASMCs), generation and D.J.F., N.L.W., R.L., M.H., Y.S., and Y.H. wrote the paper. accumulation of extracellular matrix, and local expression of The authors declare no conflict of interest. proinflammatory cytokines and chemokines and the subsequent This article is a PNAS Direct Submission. M.G.V.H. is a guest editor invited by the infiltration of leukocytes to the perivascular areas of the lung Editorial Board. (1–3). The mechanisms underlying these pathologies remain Published under the PNAS license. poorly understood, and currently available therapeutic agents 1M.H., Y.S., and Y.H. contributed equally to this work. have limited efficacy against the pathologic remodeling, despite 2To whom correspondence may be addressed. Email: [email protected], ysu@ the accumulation of a large body of extensive research over the augusta.edu, or [email protected]. past decade (1, 2, 4). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. Aberrant metabolism, especially aerobicglycolysisortheWarburg 1073/pnas.1821401116/-/DCSupplemental. effect, has been proposed as an important pathogenic mechanism in www.pnas.org/cgi/doi/10.1073/pnas.1821401116 PNAS Latest Articles | 1of10 Downloaded by guest on September 27, 2021 many glycolytic enzymes and glycolysis-related molecules or regu- lators such as glucose transporter 1 (GLUT1) and 6-phosphofructo- 2-kinase/fructose-2,6-bisphosphatases (PFKFBs) has been observed in many of the aforementioned lung cells under hypertensive con- ditions (5, 7–10). Despite these associations, the functional impor- tance of these glycolytic enzymes or regulators in the development of PH has not yet been determined. Among the numerous glycolytic regulators, PFKFB enzymes catalyze the synthesis of fructose-2,6-bisphosphate (F-2,6-P2), which is the most potent allosteric activator of 6-phosphofructo- 1-kinase (PFK-1), one of three rate-limiting enzymes for glycolysis (12). Among the four isoforms of PFKFBs, expression of the PFKFB3 isoform is dominant in vascular cells, leukocytes, and many transformed cells (12, 13). Compared with the other PFKFB isoforms, PFKFB3 has the highest kinase-to-phosphatase ratio (740:1) and controls the steady-state concentration of F-2,6-P2 in the cells (12). Recent studies indicated that blockade or deletion of endothelial PFKFB3 reduces pathological angiogenesis (14, 15). Moreover, PFKFB3 knockdown or inhibition in cancer cells substantially inhibits cell survival, growth, and invasiveness (16). However, it is unclear whether this critical glycolytic regulator plays an important role in the development of PH. Pulmonary endothelial cells are directly involved in the de- velopment and progression of PH, i.e., in the early and late stages of the disease. As such, pulmonary vasoconstriction during the early stages of PH has been attributed to endothelial dys- function (1, 2), and plexiform lesions of late-stage PH result from excessive proliferation of endothelial cells (1, 2). Recent studies using genetically modified mice have shown that excessive endo- thelial inflammation mediated by hypoxia-inducible factor-2α (HIF-2α, HIF2A), prolyl hydroxylase domain-containing
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