An IL6-STAT3-MR-FGF21 Axis Mediates Heart-Liver Crosstalk after Myocardial Infarction

The liver plays a protective role in myocardial infarction (MI). However, very little is known about the mechanisms. Here, we identify mineralocorticoid receptor (MR) as a pivotal nexus that conveys communications between the liver and the heart during MI. On one hand, hepatocyte MR deficiency and MR antagonist spironolactone both improve cardiac repair after MI through regulation on hepatic fibroblast growth factor 21 (FGF21), illustrating an MR/FGF21 axis that underlies the liver-to-heart protection against MI. On the other hand, an upstreaming acute interleukin-6 (IL6) / signal transducer and activator of transcription 3 (STAT3) pathway transmits the heart-to-liver signal to suppress MR expression after MI. Hepatocyte IL6 receptor (IL6R) deficiency and STAT3 deficiency both aggravate cardiac injury through their regulation on the MR/FGF21 axis. Therefore, we have unveiled an IL6/STAT3/MR/FGF21 signaling axis that mediates heart-liver crosstalk during MI. Targeting the signaling axis and the crosstalk may provide novel strategies to treat MI and heart failure. Overall design: Liver mRNA profiles of wild type and HMRKO mice 1 day after MI or sham operation, and liver mRNA profiles of wild type 12 hours after MI or sham operation