Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33.
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 antihypertrophic and antifibrotic effects in the myocardium. In contrast, soluble ST2 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. Here we report 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 study reveals that endothelial cell secretion of IL-33 is crucial for translating myocardial pressure overload into a selective systemic inflammatory response.
Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; Cardiovascular Division, Department of Medicine, and Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Boston, MA 02115; and.
Wei-Yu
WY
Chen
Cardiovascular Division, Department of Medicine, and Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Boston, MA 02115; and.
Jaewoo
J
Hong
Cardiovascular Division, Department of Medicine, and Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Boston, MA 02115; and.
Joseph
J
Gannon
Cardiovascular Division, Department of Medicine, and Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Boston, MA 02115; and.
Rahul
R
Kakkar
Cardiovascular Division, Department of Medicine, and Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Boston, MA 02115; and Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02139 rlee@partners.org.
Richard T
RT
Lee
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006973:Hypertension / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D018123:Receptors, Interleukin / Q000235:genetics / Q000502:physiology
C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin
cardiac hypertrophy; endothelial cells; inflammation; interleukin-33