Targeting Interleukin-8–Mediated Cellular Crosstalk Reverses Hypertrophic Cardiomyopathy and Cardiac Fibrosis in Noonan Syndrome
Year: 2026
Type: article
Abstract: BACKGROUND: Genetic variants in components or regulators of the RAS-mitogen-activated protein kinase (RAS-MAPK) signaling pathway are causative for severe and early-onset hypertrophic cardiomyopathy (HCM) in patients with Noonan syndrome (NS). Despite paracrine communication being considered to play a pivotal role in the etiology of cardiomyopathies, there is a paucity of knowledge about the underlying pathomechanism that leads to the development of HCM and cardiac fibrosis in NS. METHODS: deficiency alongside induced pluripotent stem cells derived from patients with NS with pathogenic variants in key RAS-MAPK genes and analyzed these cells and tissues at the molecular, cellular, and functional levels. RESULTS: Our findings revealed that cytokine-mediated cellular crosstalk between cardiac fibroblasts and cardiomyocytes, predominantly activated in the disease state, serves as a primary driver of the disease. Cardiac fibroblast-specific IL-8 (interleukin-8) secretion induced fibrosis-related signatures, tissue stiffness, cardiomyocyte hypertrophy, and hypercontractility, identifying dysregulated IL-8 as a heart-autonomous signaling molecule independent of inflammation and immune cell involvement. Inhibition of IL-8-CXCR1 signaling by reparixin reversed the pathological effects in cardiac fibroblasts and cardiomyocytes. CONCLUSIONS: These data provide evidence that targeting aberrant IL-8-CXCR1 signaling may be an effective therapeutic option for patients with NS-associated HCM.
Source: Circulation
Authors: Jakob Fell, Mario G. Pavez-Giani, Fabian Koitka, George Kensah, Gabriela Leao Santos, Emiel P.C. van der Vorst, Christof Lenz, Gabriela Salinas, Alexandra Victoria Busley, Alisa Fedorenko, Robin Hindmarsh, Cordula Maria Wolf, Susanne Lutz, Gerd Hasenfuss, Wolfram-Hubertus Zimmermann, Bernd Wollnik, Lukas Cyganek
Institutions: Multiscale Bioimaging, University of Göttingen, University of Basel, University Hospital of Basel, Universitätsmedizin Göttingen, Universitätsklinikum Aachen, Ludwig-Maximilians-Universität München, RWTH Aachen University, Deutsches Herzzentrum München, Technical University of Munich, Fraunhofer Institute for Translational Medicine and Pharmacology
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7154626903