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    JR Congenital Moleculare PAH

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    Liya Suwarni
    1) PAH is associated with genetic abnormalities in the BMPR2 signaling pathway and an impaired metabolic and inflammatory state in the vessel wall. 2) Dysfunctional endothelial cells release factors that stimulate smooth muscle cell proliferation, contributing to thickening of pulmonary arteries. 3) Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) disrupt critical functions like ligand binding and Smad signaling pathways.

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    JR Congenital Moleculare PAH

    Uploaded by

    Liya Suwarni
    23 views19 pages
    1) PAH is associated with genetic abnormalities in the BMPR2 signaling pathway and an impaired metabolic and inflammatory state in the vessel wall. 2) Dysfunctional endothelial cells release factors that stimulate smooth muscle cell proliferation, contributing to thickening of pulmonary arteries. 3) Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) disrupt critical functions like ligand binding and Smad signaling pathways.

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    1) PAH is associated with genetic abnormalities in the BMPR2 signaling pathway and an impaired metabolic and inflammatory state in the vessel wall. 2) Dysfunctional endothelial cells release factors that stimulate smooth muscle cell proliferation, contributing to thickening of pulmonary arteries. 3) Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) disrupt critical functions like ligand binding and Smad signaling pathways.

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    23 views19 pages

    JR Congenital Moleculare PAH

    Uploaded by

    Liya Suwarni
    1) PAH is associated with genetic abnormalities in the BMPR2 signaling pathway and an impaired metabolic and inflammatory state in the vessel wall. 2) Dysfunctional endothelial cells release factors that stimulate smooth muscle cell proliferation, contributing to thickening of pulmonary arteries. 3) Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) disrupt critical functions like ligand binding and Smad signaling pathways.

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    © All Rights Reserved
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    Download as pptx, pdf, or txt
    of 19

    Molecular Pathogenesis of Pulmonary

    Arterial Hypertension

    Presented by:

    dr. Aditya Reza Pratama*


    Supervisor:

    dr. Heny Martini, Sp.JP (K)**

    * PPDS-1 Jantung dan Pembuluh Darah FKUB/RSSA


    **Supervisor Jantung dan Pembuluh Darah FKUB/RSSA
    Introduction
    o Recent clinical and experimental studies are redefining the cellular and molecular bases of
    pulmonary arterial hypertension (PAH)
    o The genetic abnormalities first identified in association with the idiopathic form of PAH
    o Experimental and clinical studies now converge on the intersections between a genetic
    predisposition involving the BMPR2 signaling pathway and an impaired metabolic and
    chronic inflammatory state in the vessel wall
    o These deranged process culminate in an exuberant proliferative response that occludes
    the pulmonary arterial (PA) lumen and obliterates the most distal intraacinar vessels
    o Describe emerging therapies based on preclinical studies that address these address these
    converging pathways
    Pathological features of PAH
    PAH is diagnosed by an elevation in mean pulmonary arterial pressure
    above 25 mmHg at rest or 30 mmHg with exercise

    In neonates and in infants, PAH likely results from failure of the


    neonatal pulmonary vasculature to dilate at birth, and pathological
    changes in the blood vessels are evident in the first few days of life

    Increase in Tie2 receptor expression in ECs releases serotonin,


    mediating SMC proliferation
    Dysfunctional ECs release factors stimulate SMC proliferation (FGF-2), or fail to
    produce agents suppress proliferation of SMCs in response to growth factors, such as
    apelin (encoded by Apln)

    Muscularization of distal, normally nonmuscular, PAs at the alveolar duct and wall level
    differentiation of pericytes into SMCs that subsequently proliferate.

    The progressive thickening of the wall of more proximal intraacinar and preacinar
    muscular arteries and the obliteration neointimal formation increased proliferation and
    migration of cells considered to be SMCs α-SMA positive

    The loss of distal PAs by alterations in ECs and/or pericytes apoptosis
    Pathological features of PAH
    Genetics of PAH: BMPR2 and Other
    TGF-β Family Members

    abnormalities throughout the pulmonary circulation

    abnormal muscularization of distal and medial


    precapillary arteries,

    loss of precapillary arteries,

    thickening of large PAs,

    neointimal formation that is particularly occlusive in


    vessels less than 500–100 μM and in plexiform
    lesions therein
    Heterozygous for a mutation in bone morphogenetic protein (BMP) receptor
    type 2 (BMPR2)

    Mutations different functions of BMPR2, namely the ligand-binding


    domain, the signaling mechanism, and the interaction of the receptor with
    the cytoskeleton.

    BMPR2 signaling, Smad activation, and the processing of microRNAs (39),


    particularly miR-21can control functions critical to SMC contractility
    BMPR2 and Vascular Cell Dysfunction
    RNA interference in PA ECs  loss of BMPR2 apoptosis

    the reduced number of peripheral alveolar duct and wall PAs

    activate the canonical Wnt signaling pathway to induce PA

    EC survival and proliferation and activate the noncanonical pathway to


    induce migration, critical features in angiogenesis and regeneration of
    damaged blood vessels
    Drugs and Toxins
    Additive effects of serotonin and the anorexigen
    dexfenfluramine

    Seratonin and 17β-estradiol levels

    HIV, cocaine abuse, and heightened activity of


    PDGF
    Serotonin Receptors and
    Transporters
    Increased activity
    of the serotonin
    transporter

    PDGF-mediated
    proliferation of
    SMCs

    Enhances PDGF
    receptor β–
    mediated
    signaling
    Increased in
    Increase in
    neointimal lesions
    S100A4, a member Proliferation and
    from patients with
    Serotonin of the S100 family migration of PA
    IPAH and PAH
    of calcium-binding SMCs
    associated with
    proteins
    other conditions
    Inflammation and Immune Mechanisms

    a subset of patients with HIV infection  function of the


    patient’s HLA class II alleles

    expression of HHV8 (associated with Kaposi sarcoma) and


    IPAH lysosome-mediated degradation of BMPR2

    Allergic responses to ovalbumin or to Aspergillus species

    IL-13–mediated increase in α-resistin SMC proliferation

    lacking prostaglandin synthaseallergic inflammation


    Elastase Activity
    Serum and EC factors

    the cells’ production of serine elastase

    Release growth factors from the extracellular matrix and induce production of matrix
    metalloproteinases and tenascin-C, a glycoprotein

    Activation of SMC growth factor receptors and survival pathways


    Glycolytic Metabolism and The Warburg Effect

    achieved through the


    pyruvate
    dehydrogenase
    reduced cytochrome
    kinase (PDK) inhibitor
    c oxidase and SOD
    dicholoracetate
    levels and impaired
    (DCA)
    Kv channel
    normoxic expression and
    stimulation of HIF- function
    1α (a phenomenon
    known as the
    Warburg effect),
    Hyperpolarized
    mitochondria
    Gender and estrogen metabolism

    aberrant expression of a cytochrome, CYP1B1 a mitogenic estrogen


    metabolite

    estrogen and activation of the estrogen receptor β (ERβ) is protective


    against the development of experimental pulmonary hypertension

    lack of insulin resistance and of PAH in Apoe–/–low level of adiponectin


    in males testosterone-mediated degradation
    Stem and Progenitor Cells

    Circulating EPCs and endothelial derived autocrine signals

    Mesenchymal cells  attenuate experimentally induced


    PAH and improve RV performance

    BMPR2 mutations PAH influence the remodeling


    pathology of proximal PAs and of cardiac myocytes and
    fibroblasts
    Conclusion
    BMPR2 signaling pathway in vascular and in inflammatory/immune
    cells

    Response of the tissue to an infectious or inflammatory stimulus

    Inflammation and oxidative stress  mitochondrial metabolism and


    gene regulation

    The use of induced pluripotent stem cells differentiated into vascular


    cells could be useful
    Pulmonary Hypertension
    THANK YOU
    For Your Attention

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