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Editorial
. 2017 Dec 19;136(25):2486-2490.
doi: 10.1161/CIRCULATIONAHA.117.031655.

Pyruvate Kinase and Warburg Metabolism in Pulmonary Arterial Hypertension: Uncoupled Glycolysis and the Cancer-Like Phenotype of Pulmonary Arterial Hypertension

Stephen L Archer  1
Affiliations
Editorial

Pyruvate Kinase and Warburg Metabolism in Pulmonary Arterial Hypertension: Uncoupled Glycolysis and the Cancer-Like Phenotype of Pulmonary Arterial Hypertension

Stephen L Archer. Circulation. .
No abstract available

Keywords: DNA methylation; Editorials; bone morphogenetic protein receptors, type II; extracellular signal-related MAP kinases; glycolysis.

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Figures

Figure 1
Figure 1. A Growing Cast of Warburg Mediators
A: The new cast: Decreased miR-124 expression and/or BMPR2 downregulation increases PTBP1 expression which alters PK splicing creating a PKM2/PKM1 ratio increase that favours uncoupled glycolysis (Warburg metabolism). This metabolic shift is associated with endothelial cell and fibroblast proliferation. The nuclear effects of PKM2, as a regulator of histone phosphorylation and potentiator of HIF-1α activation, were not studied. Likewise, PKM2’s ability to promote cell proliferation by activating ERK1/2 was not assessed. An oxidant environment, such as elevated H2O2 levels, inhibits PKM2 activity. B) The old cast: Increased lung specific activation of DNMT 1 and 3b methylate the SOD2 promoter and reduce SOD2 levels and ETC 1 activity. This impairs oxygen sensing and leads to normoxic HIF-1α activation. HIF-1α increases PDK expression and promotes PASMC proliferation. In addition, increased expression of miR25 and miR138 decrease function of the mitochondrial calcium uniporter complex (MCUC). This suppresses MCUC function-raises cytosolic calcium and lowers intramitochondrial calcium-causes vasoconstriction and impairs PDH activity. Loss of the MCU function also causes mitochondrial fission. These effects together promote PASMC proliferation and inhibits apoptosis. PDH also translocates to the nucleus where it regulates histone acetylation. Finally decreases in miR-204 increase expression of bromodomain containing protein 4 (BRD4) that binds to acetylated histone via its tandem bromodomains . This activates nuclear factor of activated T cells (NFAT) and survivin.
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References

    1. Archer SL. Mitochondrial dynamics--mitochondrial fission and fusion in human diseases. The New England journal of medicine. 2013;369:2236–51. - PubMed
    1. Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, Dyck JR, Gomberg-Maitland M, Thebaud B, Husain AN, Cipriani N, Rehman J. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation. 2010;121:2661–71. - PMC - PubMed
    1. Hong Z, Chen KH, DasGupta A, Potus F, Dunham-Snary K, Bonnet S, Tian L, Fu J, Breuils-Bonnet S, Provencher S, Wu D, Mewburn J, Ormiston ML, Archer SL. MicroRNA-138 and MicroRNA-25 Down-regulate Mitochondrial Calcium Uniporter, Causing the Pulmonary Arterial Hypertension Cancer Phenotype. Am J Respir Crit Care Med. 2017;195:515–529. - PMC - PubMed
    1. Meloche J, Potus F, Vaillancourt M, Bourgeois A, Johnson I, Deschamps L, Chabot S, Ruffenach G, Henry S, Breuils-Bonnet S, Tremblay E, Nadeau V, Lambert C, Paradis R, Provencher S, Bonnet S. Bromodomain-Containing Protein 4: The Epigenetic Origin of Pulmonary Arterial Hypertension. Circ Res. 2015;117:525–35. - PubMed
    1. Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL. Acute oxygen-sensing mechanisms. The New England journal of medicine. 2005;353:2042–55. - PMC - PubMed