> Detailanzeige

Jaffré, Fabrice; Miller, Clint L.; Schänzer, Anne; Evans, Todd; Roberts, Amy E.; Hahn, Andreas; Kontaridis, Maria I.

Inducible Pluripotent Stem Cell–Derived Cardiomyocytes Reveal Aberrant Extracellular Regulated Kinase 5 and Mitogen-Activated Protein Kinase Kinase 1/2 Signaling Concomitantly Promote Hypertrophic Cardiomyopathy in RAF1 -Associated Noonan Syndrome

Literatur-
verwaltung

Zur
Merkliste

Lösche von
Merkliste

Per Whatsapp teilen

Schließen

Merkliste



Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
  • Medientyp: E-Artikel
  • Titel: Inducible Pluripotent Stem Cell–Derived Cardiomyocytes Reveal Aberrant Extracellular Regulated Kinase 5 and Mitogen-Activated Protein Kinase Kinase 1/2 Signaling Concomitantly Promote Hypertrophic Cardiomyopathy in RAF1 -Associated Noonan Syndrome
  • Beteiligte: Jaffré, Fabrice; Miller, Clint L.; Schänzer, Anne; Evans, Todd; Roberts, Amy E.; Hahn, Andreas; Kontaridis, Maria I.
  • Erschienen: Ovid Technologies (Wolters Kluwer Health), 2019
  • Erschienen in: Circulation
  • Sprache: Englisch
  • DOI: 10.1161/circulationaha.118.037227
  • ISSN: 0009-7322; 1524-4539
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec> <jats:title>Background:</jats:title> <jats:p> More than 90% of individuals with Noonan syndrome (NS) with mutations clustered in the CR2 domain of <jats:italic>RAF1</jats:italic> present with severe and often lethal hypertrophic cardiomyopathy (HCM). The signaling pathways by which NS <jats:italic>RAF1</jats:italic> mutations promote HCM remain elusive, and so far, there is no known treatment for NS-associated HCM. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p> We used patient-derived <jats:italic> RAF1 <jats:sup>S257L/+</jats:sup> </jats:italic> and CRISPR-Cas9–generated isogenic control inducible pluripotent stem cell (iPSC)–derived cardiomyocytes to model NS <jats:italic>RAF1</jats:italic> -associated HCM and to further delineate the molecular mechanisms underlying the disease. </jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> We show that mutant iPSC–derived cardiomyocytes phenocopy the pathology seen in hearts of patients with NS by exhibiting hypertrophy and structural defects. Through pharmacological and genetic targeting, we identify 2 perturbed concomitant pathways that, together, mediate HCM in <jats:italic>RAF1</jats:italic> mutant iPSC–derived cardiomyocytes. Hyperactivation of mitogen-activated protein kinase kinase 1/2 (MEK1/2), but not extracellular regulated kinase 1/2, causes myofibrillar disarray, whereas the enlarged cardiomyocyte phenotype is a direct consequence of increased extracellular regulated kinase 5 (ERK5) signaling, a pathway not previously known to be involved in NS. RNA-sequencing reveals genes with abnormal expression in <jats:italic>RAF1</jats:italic> mutant iPSC–derived cardiomyocytes and identifies subsets of genes dysregulated by aberrant MEK1/2 or ERK5 pathways that could contribute to the NS-associated HCM. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p> Taken together, the results of our study identify the molecular mechanisms by which NS <jats:italic>RAF1</jats:italic> mutations cause HCM and reveal downstream effectors that could serve as therapeutic targets for treatment of NS and perhaps other, more common, congenital HCM disorders. </jats:p> </jats:sec>
  • Zugangsstatus: Freier Zugang