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
Year: 2019
Type: article
Abstract: BACKGROUND: More than 90% of individuals with Noonan syndrome (NS) with mutations clustered in the CR2 domain of RAF1 present with severe and often lethal hypertrophic cardiomyopathy (HCM). The signaling pathways by which NS RAF1 mutations promote HCM remain elusive, and so far, there is no known treatment for NS-associated HCM. METHODS: and CRISPR-Cas9-generated isogenic control inducible pluripotent stem cell (iPSC)-derived cardiomyocytes to model NS RAF1-associated HCM and to further delineate the molecular mechanisms underlying the disease. RESULTS: 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 RAF1 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 RAF1 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. CONCLUSIONS: Taken together, the results of our study identify the molecular mechanisms by which NS RAF1 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.
Source: Circulation
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Role of RhoA in the Molecular Pathogenesis of Heart Disease., A Gata456 Pipeline of Discovery, Deciphering novel molecular mechanisms underlying hypertrophic cardiomyopathy in Noonan syndrome using iPS cells, Targeted inhibition of fibrosis for the prevention of heart failure, Elucidating the Phosphatase-Independent Roles of PTPN11 in the Heart, EPISTATIC REGULATORY MECHANISMS OF CORONARY HEART DISEASE RISK
OpenAlex ID: W2955764872