3/9/2019 Cytokine Profile Clusters Are Represented Across all Forms - - PowerPoint PPT Presentation

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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

SLIDE 1

3/9/2019 1

The Pulmonary Arterial Hypertension Basic Science Year in Review

Cell and Molecular Biology Inflammation Therapy

Cytokine Profile Clusters Are Represented Across all Forms of PAH and Cluster 1 has Worse Prognosis

Sweatt …..Zamanian Circ Res 2018 epub

Aicardi Goutieres and PAH

(Interferon overproduction) Adang…Venderver Mol Genetics Metab 125: 2018 351-358

Toll-Like Receptor 3 is a Therapeutic Target in PAH

(induces interferon)

Farkas….Thompson AJRCCM 199: -210 2918

Inability to induce interferon via TLR3 is associated with PH

Ectopic Upregulation of IL6 Receptor in PAH

Tamura…..Guignabert C JCI 128: 5, May 2018

SLIDE 2

3/9/2019 2

Sheikh….Greif Cell Rep 24: 23, 1152-65 2018

Macrophages Transdifferentiate and Fuse with Smooth Muscle Cells Natural Killer Cell Deficiency Causes PAH by Increasing IL23 Producing Macrophages

Ratsep…. Ormiston AJP Lung 315L L977-990, 2018

IL23 is associated with Th17 autoimmunity

Dominant Role for Regulatory T Cells in Protecting Females Against Pulmonary Hypertension.

Tamosiuniene R …….Nicolls MR Circ Res 2018 122: 1689-1702

Epigenetic Dysregulation of DRP1 Binding Partners Increases Mitochondrial Fission in PAH Chen……Archer 138:287-304, Circulation 2018

SLIDE 3

3/9/2019 3

Wnt 5a in Exosomes Recruits Pericytes to Establish Normal Vessels and is Deficient in PAH Loss of Wnt 5a in Mice Causes Pulmonary Hypertension

Yuan ….de Jesus Perez: Circulation (2018 epub)

A Potential Role for Exosomal Translationally Controlled Tumor Protein Export in Vascular Remodeling in Pulmonary Arterial Hypertension

Ferrer Morrell AJRCCM 59: 467-478, 2018

NEDD9 targets COL3A1 to Promote Endothelial Fibrosis and Pulmonary Arterial Hypertension

Samokhin….. Maron BR Science Trans Med 10: 2018,

NEDD9 Interacts with SMAD3 to induce Collagen Production

Bone Marrow–Derived Proangiogenic Cells Mediate Pulmonary Arteriole Stiffening via Serotonin 2B Rec.-Dep. Mechanism

Bloodworth…Merryman Circ Res 2018 123 e51-61

SLIDE 4

3/9/2019 4

Smooth Muscle Contact Drives Endothelial Regeneration by BMPR2-Notch1 Mediated Metabolic and Epigenetic Changes

Miyagawa,,,,Rabinovitch, Circ Res, Feb 2019, 124: 211-224

Evolution of Hemodynamic Forces in the Pulmonary Tree with Progressive Worsening of Pulmonary Hypertension

Yang….Marsden, Feinstein Biomechanics and Modeling in Mechanobiology Jan 2019

Ovine Models of Congenital Heart Disease and Consequences of Hemodynamic Alterations on Pulmonary Vascular Remodeling

Johnson-Kameny….Fineman AJRCMB January 2019

Converging Paths of Pulmonary Arterial Hypertension and Cellular Senescence

Van der Feen, Berger, Bartelds AJRCMB Feb 2019

SLIDE 5

3/9/2019 5

PPARg Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis

Li…. Rabinovitch, Cell Reports January 2019

PPARG Agonist Pioglitazone Reverses Pulmonary Hypertension and Prevents Right Heart Failure via Fatty Acid Oxidation

Legchenko…..Hansmann Sci Trans Med 2018 10: 438

Morrell et al: Eur Resp J 180: 1899, 2019

Approaches to PAH Treatment by Enhancing BMPR2 Signaling BMP9

Germline BMP9 Mutation Causes Idiopathic Pulmonary Hypertension

Wang….Jing Eur Resp J 2018 in press Nickolic ,….Yu AJRCCM in press, 2018

BMP9 is a Mechanistic Biomarker of Portopulmonary Hypertension Selective BMP-9 Inhibition Partially Protects Against Experimental PH

Tu….Guignabert Circ Res 2019

SLIDE 6

3/9/2019 6

FHIT, a Novel Modifier Gene in Pulmonary Arterial Hypertension.

Dannewitz-Prosseda…..Spiekerkoetter AJRCCM 2019 199: 83-98

Conclusions

Inflammation: 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

Cell and Molecular Biology Wnt 5a is released from endothelial cells to recruit pericytes and is deficient in PH, related to instability of microvessels. NEDD9 is a gene that accounts for accumulation of collagen and vascular stiffness in pulmonary hypertension PPAR gamma protects against DNA damage by activating ATM, the first responder BMPR2 activates Notch to allow for endothelial regeneration and Notch meditated metabolism coordinates chromatin remodeling & gene regulation Endothelial exosomes containing TCTP induce SMC proliferation Transcriptomic analysis details adverse effects of newborn shunt PH model suggests dysregulation of endothelial cells

Conclusions

Low BMP9 is a biomarker of PAH, BMP9 mutation is associated with PAH and BMP9 may be effective but needs titration to avoid adverse effects Increasing –FHIT increases BMPR2 expression and reduces PH PPAR agonists (pioglitazone) may improve right heart function Senolytic (anti-aging) therapy may be of benefit in CHD-PAH Therapeutics

SLIDE 7

3/9/2019 7

Rare variants in SOX17 are Associated with Pulmonary Arterial Hypertension with Congenital Heart Disease

Zhu…..Chung W Genome Medicine 2018 10:56

3/9/2019 1

The Pulmonary Arterial Hypertension Basic Science Year in Review

Cell and Molecular Biology Inflammation Therapy

Cytokine Profile Clusters Are Represented Across all Forms of PAH and Cluster 1 has Worse Prognosis

Aicardi Goutieres and PAH

Toll-Like Receptor 3 is a Therapeutic Target in PAH

Ectopic Upregulation of IL6 Receptor in PAH

3/9/2019 2

Macrophages Transdifferentiate and Fuse with Smooth Muscle Cells Natural Killer Cell Deficiency Causes PAH by Increasing IL23 Producing Macrophages

IL23 is associated with Th17 autoimmunity

Dominant Role for Regulatory T Cells in Protecting Females Against Pulmonary Hypertension.

Epigenetic Dysregulation of DRP1 Binding Partners Increases Mitochondrial Fission in PAH Chen……Archer 138:287-304, Circulation 2018

3/9/2019 3

Wnt 5a in Exosomes Recruits Pericytes to Establish Normal Vessels and is Deficient in PAH Loss of Wnt 5a in Mice Causes Pulmonary Hypertension

A Potential Role for Exosomal Translationally Controlled Tumor Protein Export in Vascular Remodeling in Pulmonary Arterial Hypertension

NEDD9 targets COL3A1 to Promote Endothelial Fibrosis and Pulmonary Arterial Hypertension

NEDD9 Interacts with SMAD3 to induce Collagen Production

Bone Marrow–Derived Proangiogenic Cells Mediate Pulmonary Arteriole Stiffening via Serotonin 2B Rec.-Dep. Mechanism

3/9/2019 4

Smooth Muscle Contact Drives Endothelial Regeneration by BMPR2-Notch1 Mediated Metabolic and Epigenetic Changes

Evolution of Hemodynamic Forces in the Pulmonary Tree with Progressive Worsening of Pulmonary Hypertension

Ovine Models of Congenital Heart Disease and Consequences of Hemodynamic Alterations on Pulmonary Vascular Remodeling

Converging Paths of Pulmonary Arterial Hypertension and Cellular Senescence

3/9/2019 5

PPARg Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis

PPARG Agonist Pioglitazone Reverses Pulmonary Hypertension and Prevents Right Heart Failure via Fatty Acid Oxidation

Morrell et al: Eur Resp J 180: 1899, 2019

Approaches to PAH Treatment by Enhancing BMPR2 Signaling BMP9

Germline BMP9 Mutation Causes Idiopathic Pulmonary Hypertension

BMP9 is a Mechanistic Biomarker of Portopulmonary Hypertension Selective BMP-9 Inhibition Partially Protects Against Experimental PH

3/9/2019 6

FHIT, a Novel Modifier Gene in Pulmonary Arterial Hypertension.

Conclusions

Inflammation: 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

3/9/2019 7

Rare variants in SOX17 are Associated with Pulmonary Arterial Hypertension with Congenital Heart Disease

Immunosuppressant Tacrolimus (FK506) and Elastase Inhibitor Elafin Amplify a Weak BMPR2 Signal pERK , pSMAD signals and gene expression

BMP BMP BMP

P

FK506 removes FKBP12 & blocks calcineurin to amplify a weak signal

P

Reduced BMPR2

BMP

FK506

Reduced BMPR2

P

BMP

Elafin retains BMPR2 in caveoli to amplify a weak signal

Normal BMPR2