TY - JOUR
T1 - Cardiac macrophages promote diastolic dysfunction
AU - Hulsmans, Maarten
AU - Sager, Hendrik B.
AU - Roh, Jason D.
AU - Valero-Muñoz, María
AU - Houstis, Nicholas E.
AU - Iwamoto, Yoshiko
AU - Sun, Yuan
AU - Wilson, Richard M.
AU - Wojtkiewicz, Gregory
AU - Tricot, Benoit
AU - Osborne, Michael T.
AU - Hung, Judy
AU - Vinegoni, Claudio
AU - Naxerova, Kamila
AU - Sosnovik, David E.
AU - Zile, Michael R.
AU - Bradshaw, Amy D.
AU - Liao, Ronglih
AU - Tawakol, Ahmed
AU - Weissleder, Ralph
AU - Rosenzweig, Anthony
AU - Swirski, Filip K.
AU - Sam, Flora
AU - Nahrendorf, Matthias
N1 - Publisher Copyright:
© 2018 Hulsmans et al.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic 18 F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction.
AB - Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic 18 F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction.
UR - http://www.scopus.com/inward/record.url?scp=85041385587&partnerID=8YFLogxK
U2 - 10.1084/jem.20171274
DO - 10.1084/jem.20171274
M3 - Article
C2 - 29339450
AN - SCOPUS:85041385587
SN - 0022-1007
VL - 215
SP - 423
EP - 440
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
ER -