Elastase Mediated Pulmonary Vascular Disease. Elastase
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1 PPH Newborn Autoimmune Heart defect Lung abnormality Pathology of Pulmonary Arterial Hypertension () Endothelial and Smooth Muscle Dysfunction Liver disease portal hyper. Pulmonary Hypertension Infectious: HIV, schistosomiasis? Sickle cell Substance abuse Normal PA Endothelial Cell (PAEC) PASMC proliferation EC apoptosis Idiopathic PA Smooth Muscle (PASMC) Degradation of Elastin Precedes & Associates with Severe Pulmonary Vascular Changes Mediated Pulmonary Vascular Disease Normal PA PA w/ Neointimal Lesion Endo. cell first casualty Endo. injury Serum leak Degradation of elastin Release of growth factors muscularization SMC Migration Loss of elastin: Increases vascular stiffness Promotes SMC proliferation and obliterative changes Leads to vulnerability of the distal microcirculation Loss of arteries Apoptosis Activity Progression of : Inhibition of Reverses Pathology Inhibitors (EI)Reverse PVD Induced by Toxin, in Rats Growth Factors Metallo- proteinases Day 21 norx 1K=EI Pro- inflammatory elastin peptides Tenascin-C SMC Progression GF receptor activation cell survival SMC Apoptosis Regression Veh Kyle Cowan, Nat Med. 2 M249=EI 1
2 Activity Induces PA Hypertension Growth Factor Receptor Blockade (PKI166) Reverses Induced PA Hypertension Growth Factors SMC Progression Metallo- proteinases Pro- inflamm peptides Tenascin-C GF receptor activation cell survival SMC Apoptosis Regression Mean PAP (mmhg) (n=8-13) p<.1 vs Vehicle * Saline Vehicle PKI166 Sandra Merklinger, Circulation, RVH RV/(LV+S) 4 (%) 2 * Saline Vehicle PKI166 Blockade with Imatinib Beneficial in Patients with Very High Pulmonary Vascular Resistance -Induced Medial Hypertrophy vs. Neointimal Formation in Clinical Tissue QuickTime and a decompressor are needed to see this picture. Clincal Ghofrani et al: AJRCCM, 21..n = per group Needed: a rodent model of PA neointimal lesions S1A4(Mts-1) 1) Over-expressing expressing Mouse has Advanced Neointimal Lesions Hypothesis: Virus-Induced Degrades Susceptible Elastin & Released Elastin Peptides & GF Cause Neointima S1A4 mouse Wild Type mouse Wild Type S1A4 O/E MHV68 infection A. Susceptibility of elastin to degradation B. Heightened elastase activity Smooth Muscle Cell S1A4 is highly expressed in neointimal lesions of patients (Greenway et al., 24). Elastin peptides Growth factors Neointima 2
3 Mutant Receptor in Idiopathic What Promotes Beneficial Response to Injury? -RII 2,4,7 -RIA + Growth Factors Promote Adverse Remodeling Ability to activate the RII receptor! Mutated BmprII in 7%familial and 2% sporadic idiopathic PH Reduced RII+ IA expression in all forms of Transcription (regulatory) factors Bone Morphogenetic Protein Signaling Prevents Adverse Remodeling RII target genes? RIA Inhibits PA SMC Growth via Circulation 27, J Clin Invest 28 Injury: mediated release of growth factors, e.g., Adiponectin receptor Dr. George Hansmann Promotes PAEC survival and neoangiogenesis Inhibits PASMC proliferation Prevent SMC proliferation Inhibits r signal Pro-proliferative perk Cell cycle inhibitors. P27,P21 A -Antagonist Antagonist Prevents the Antiproliferative Effect of -2 2 in Human PASMC Cell Number 6x1 3 4x1 3 2x1 3 *** *** vehicle -BB -2 vehicle = GW9662 (1μM) = irreversible antagonist ***p <.1 One-Way ANOVA n = 4 Agonist glitazone Reverses PA Hypertension and in -/- Insulin Resistant Mice RVSP (mmhg) w -/- -/- 4w p <.1 n =
4 Insulin Resistance is Increased in Female Patients Pulmonary Hypertension (Zamanian, Eur Resp J, 29) IR IR IR IR Event-Free Free Survival (%) Insulin Resistance Predicts Worse 6-Month 6 Event Free Survival in Females 1 8 Dr RohamZamanian, Eur Resp J, 29) Insulin Sensitive (N=3) 6 1 Insulin Resistant (N=37) Female Male Days γ Agonist Can Rescue Dysfunctional RII Agonist glitazone Rescues Loss of Growth Inhibition With Dysfunction of RII in PA SMC receptor agonist OD (MTT).1 RII +/- Mice *** *** I + RII mut *** ** + Cell cycle inhibitors..1 Suppress Growth Growth Factor Growth Factor Promotes Endothelial Survival and via ß-catenin ß- n Signaling Induces Complex Formation Between Transcription Factors and β-catenin RII RI Dr. Tero-Pekka Alastalo Migration β- Dr. Vinicio de Jesus Perez J Cell Biol: 29 unpublished β- Endothelial growth target genes? 4
5 Signaling Induces Complex Formation Between Transcription Factors and β-catenin RII RI Can we use a known drug to improve function of the RII receptor? Nitro- fatty acids β- β- target genes
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