Abstract
Hypertension increases the pressure load on the heart and is associated with a poorly understood chronic systemic inflammatory state. Interleukin-33 (IL-33) binds to membrane-bound ST2 (ST2L) and has anti-hypertrophic and anti-fibrotic effects in the myocardium. In contrast, soluble ST2 (sST2) appears to act as a decoy receptor for IL-33, blocking myocardial and vascular benefits and is a prognostic biomarker in patients with cardiovascular diseases. We found that a highly local intramyocardial IL-33/ST2 conversation regulates the heart’s response to pressure overload. Either endothelial-specific deletion of IL33 or cardiomyocyte-specific deletion of ST2 exacerbated cardiac hypertrophy with pressure overload. Furthermore, pressure overload induced systemic circulating IL-33 as well as systemic circulating IL-13 and TGF-beta1; this was abolished by endothelial-specific deletion of IL33 but not by cardiomyocyte-specific deletion of IL33. Our results demonstrated that endothelial cells are the major sources of systemic IL-33 induced by myocardial pressure overload. Our study reveals that endothelial cell secretion of IL33 is crucial for translating myocardial pressure overload into a selective systemic inflammatory state.
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