3/9/2019 Cytokine Profile Clusters Are Represented Across all Forms of PAH and Cluster 1 has Worse Prognosis The Pulmonary Arterial Hypertension Basic Science Year in Review Sweatt …..Zamanian Circ Res 2018 epub Cell and Molecular Biology Inflammation Therapy Toll-Like Receptor 3 is a Aicardi Goutieres and PAH Therapeutic Target in PAH Ectopic Upregulation of IL6 Receptor in PAH (induces interferon) (Interferon overproduction) Adang…Venderver Mol Genetics Metab 125: 2018 351-358 Farkas….Thompson AJRCCM 199: -210 Tamura…..Guignabert C JCI 128: 5, May 2018 2918 Inability to induce interferon via TLR3 is associated with PH 1
3/9/2019 Macrophages Transdifferentiate and Fuse with Smooth Muscle Cells Natural Killer Cell Deficiency Causes PAH by Increasing IL23 Producing Macrophages Sheikh….Greif Cell Rep 24: 23, 1152-65 2018 Ratsep…. Ormiston AJP Lung 315L L977-990, 2018 IL23 is associated with Th17 autoimmunity Dominant Role for Regulatory T Cells in Protecting Epigenetic Dysregulation of DRP1 Females Against Pulmonary Hypertension. Binding Partners Increases Mitochondrial Fission in PAH Chen……Archer 138:287-304, Circulation 2018 Tamosiuniene R …….Nicolls MR Circ Res 2018 122: 1689-1702 2
3/9/2019 A Potential Role for Exosomal Translationally Controlled Tumor Protein Wnt 5a in Exosomes Recruits Pericytes to Establish Normal Vessels Export in Vascular Remodeling in Pulmonary Arterial Hypertension and is Deficient in PAH Loss of Wnt 5a in Mice Causes Pulmonary Hypertension Ferrer Morrell AJRCCM 59: 467-478, 2018 Yuan ….de Jesus Perez: Circulation (2018 epub) NEDD9 targets COL3A1 to Promote Endothelial Fibrosis Bone Marrow–Derived Proangiogenic Cells Mediate Pulmonary Arteriole and Pulmonary Arterial Hypertension Stiffening via Serotonin 2B Rec.-Dep. Mechanism Samokhin….. Maron BR Science Trans Med 10: 2018, Bloodworth…Merryman Circ Res 2018 123 e51-61 NEDD9 Interacts with SMAD3 to induce Collagen Production 3
3/9/2019 Evolution of Hemodynamic Forces in the Pulmonary Tree with Smooth Muscle Contact Drives Endothelial Regeneration by Progressive Worsening of Pulmonary Hypertension BMPR2-Notch1 Mediated Metabolic and Epigenetic Changes Miyagawa,,,,Rabinovitch, Circ Res, Feb 2019, 124: 211-224 Yang….Marsden, Feinstein Biomechanics and Modeling in Mechanobiology Jan 2019 Ovine Models of Congenital Heart Disease and Consequences of Converging Paths of Pulmonary Arterial Hypertension Hemodynamic Alterations on Pulmonary Vascular Remodeling and Cellular Senescence Johnson-Kameny….Fineman AJRCMB January 2019 Van der Feen, Berger, Bartelds AJRCMB Feb 2019 4
3/9/2019 PPARG Agonist Pioglitazone Reverses Pulmonary Hypertension and Prevents Right Heart Failure via Fatty Acid Oxidation PPAR g Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis Legchenko…..Hansmann Li…. Rabinovitch, Cell Reports January 2019 Sci Trans Med 2018 10: 438 BMP9 Approaches to PAH Treatment by Enhancing BMPR2 Signaling Selective BMP-9 Inhibition Partially Germline BMP9 Mutation Causes Protects Against Experimental PH Idiopathic Pulmonary Hypertension Tu….Guignabert Circ Res 2019 Wang….Jing Eur Resp J 2018 in press BMP9 is a Mechanistic Biomarker of Portopulmonary Hypertension Nickolic ,….Yu AJRCCM in press, 2018 Morrell et al: Eur Resp J 180: 1899, 2019 5
3/9/2019 FHIT, a Novel Modifier Gene in Pulmonary Arterial Hypertension. Conclusions Inflammation: Dannewitz-Prosseda…..Spiekerkoetter AJRCCM 2019 199: 83-98 Cytokine profiling differs among patients regardless of PAH etiology and appears to have prognostic value Tregs and Natural Killer Cells are protective Excess IL6 receptor and excess interferon cause PAH Conclusions Conclusions Cell and Molecular Biology Wnt 5a is released from endothelial cells to recruit pericytes and Therapeutics is deficient in PH, related to instability of microvessels. Senolytic (anti-aging) therapy may be of benefit in CHD-PAH NEDD9 is a gene that accounts for accumulation of collagen and vascular stiffness in pulmonary hypertension PPAR agonists (pioglitazone) may improve right heart function PPAR gamma protects against DNA damage by activating ATM, the first responder Low BMP9 is a biomarker of PAH, BMP9 mutation is associated with PAH BMPR2 activates Notch to allow for endothelial regeneration and Notch and BMP9 may be effective but needs titration to avoid adverse effects meditated metabolism coordinates chromatin remodeling & gene regulation Endothelial exosomes containing TCTP induce SMC proliferation Increasing –FHIT increases BMPR2 expression and reduces PH Transcriptomic analysis details adverse effects of newborn shunt PH model suggests dysregulation of endothelial cells 6
3/9/2019 Immunosuppressant Tacrolimus (FK506) and Rare variants in SOX17 are Associated with Elastase Inhibitor Elafin Amplify a Weak BMPR2 Signal Pulmonary Arterial Hypertension with Congenital Heart Disease Zhu…..Chung W Genome Medicine 2018 10:56 Reduced Normal BMP Reduced BMP BMP BMP BMPR2 BMPR2 BMPR2 BMP ELAFIN Calcineurin Calcineurin P FKBP12 FKBP12 P P FK506 pERK , pSMAD FK506 Elafin retains BMPR2 signals and removes FKBP12 & in caveoli to amplify a weak signal gene expression blocks calcineurin to amplify a weak signal 7
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