Targeting Interleukin-8-Mediated Cellular Crosstalk Reverses Hypertrophic Cardiomyopathy and Cardiac Fibrosis in Noonan Syndrome.

Abstract

Genetic variants in components or regulators of the 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 hypertrophic cardiomyopathy and cardiac fibrosis in NS. 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 <i>LZTR1</i> 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. 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. These data provide evidence that targeting aberrant IL-8-CXCR1 signaling may be an effective therapeutic option for patients with NS-associated hypertrophic cardiomyopathy.