TY - JOUR
T1 - New role for interleukin-13 receptor α1 in myocardial homeostasis and heart failure
AU - Amit, Uri
AU - Kain, David
AU - Wagner, Allon
AU - Sahu, Avinash
AU - Nevo-Caspi, Yael
AU - Gonen, Nir
AU - Molotski, Natali
AU - Konfino, Tal
AU - Landa, Natalie
AU - Naftali-Shani, Nili
AU - Blum, Galia
AU - Merquiol, Emmanuelle
AU - Karo-Atar, Danielle
AU - Kanfi, Yariv
AU - Paret, Gidi
AU - Munitz, Ariel
AU - Cohen, Haim Y.
AU - Ruppin, Eytan
AU - Hannenhalli, Sridhar
AU - Leor, Jonathan
N1 - Publisher Copyright:
© 2017 The Authors.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Background- The immune system plays a pivotal role in myocardial homeostasis and response to injury. Interleukins-4 and -13 are anti-inflammatory type-2 cytokines, signaling via the common interleukin-13 receptor α1 chain and the type-2 interleukin-4 receptor. The role of interleukin-13 receptor α1 in the heart is unknown. Methods and Results- We analyzed myocardial samples from human donors (n=136) and patients with end-stage heart failure (n=177). We found that the interleukin-13 receptor α1 is present in the myocardium and, together with the complementary type-2 interleukin-4 receptor chain Il4ra, is significantly downregulated in the hearts of patients with heart failure. Next, we showed that Il13ra1-deficient mice develop severe myocardial dysfunction and dyssynchrony compared to wild-type mice (left ventricular ejection fraction 29.7±9.9 versus 45.0±8.0; P=0.004, left ventricular end-diastolic diameter 4.2±0.2 versus 3.92±0.3; P=0.03). A bioinformatic analysis of mouse hearts indicated that interleukin-13 receptor α1 regulates critical pathways in the heart other than the immune system, such as extracellular matrix (normalized enrichment score=1.90; false discovery rate q=0.005) and glucose metabolism (normalized enrichment score=-2.36; false discovery rate q=0). Deficiency of Il13ra1 was associated with reduced collagen deposition under normal and pressure-overload conditions. Conclusions- The results of our studies in humans and mice indicate, for the first time, a role of interleukin-13 receptor α1 in myocardial homeostasis and heart failure and suggests a new therapeutic target to treat heart disease.
AB - Background- The immune system plays a pivotal role in myocardial homeostasis and response to injury. Interleukins-4 and -13 are anti-inflammatory type-2 cytokines, signaling via the common interleukin-13 receptor α1 chain and the type-2 interleukin-4 receptor. The role of interleukin-13 receptor α1 in the heart is unknown. Methods and Results- We analyzed myocardial samples from human donors (n=136) and patients with end-stage heart failure (n=177). We found that the interleukin-13 receptor α1 is present in the myocardium and, together with the complementary type-2 interleukin-4 receptor chain Il4ra, is significantly downregulated in the hearts of patients with heart failure. Next, we showed that Il13ra1-deficient mice develop severe myocardial dysfunction and dyssynchrony compared to wild-type mice (left ventricular ejection fraction 29.7±9.9 versus 45.0±8.0; P=0.004, left ventricular end-diastolic diameter 4.2±0.2 versus 3.92±0.3; P=0.03). A bioinformatic analysis of mouse hearts indicated that interleukin-13 receptor α1 regulates critical pathways in the heart other than the immune system, such as extracellular matrix (normalized enrichment score=1.90; false discovery rate q=0.005) and glucose metabolism (normalized enrichment score=-2.36; false discovery rate q=0). Deficiency of Il13ra1 was associated with reduced collagen deposition under normal and pressure-overload conditions. Conclusions- The results of our studies in humans and mice indicate, for the first time, a role of interleukin-13 receptor α1 in myocardial homeostasis and heart failure and suggests a new therapeutic target to treat heart disease.
KW - Cytokine
KW - Heart failure
KW - Receptor
UR - http://www.scopus.com/inward/record.url?scp=85019357367&partnerID=8YFLogxK
U2 - 10.1161/JAHA.116.005108
DO - 10.1161/JAHA.116.005108
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AN - SCOPUS:85019357367
SN - 2047-9980
VL - 6
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 5
M1 - e005108
ER -