靶向白介素-8介导的细胞通讯可逆转努南综合征中的肥厚型心肌病和心脏纤维化

原文

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: To dissect the impact of noncardiomyocytes in the development of NS, we employed two-dimensional and three-dimensional human induced pluripotent stem cell models of LZTR1 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.