1. Interleukin 11 therapy causes acute left ventricular dysfunction.
- Author
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Sweeney M, O'Fee K, Villanueva-Hayes C, Rahman E, Lee M, Tam CN, Pascual-Navarro E, Maatz H, Lindberg EL, Vanezis K, Ramachandra CJ, Andrew I, Jennings ER, Lim WW, Widjaja AA, Carling D, Hausenloy DJ, Hübner N, Barton PJR, and Cook SA more...
- Subjects
- Animals, STAT3 Transcription Factor metabolism, STAT3 Transcription Factor genetics, Janus Kinases metabolism, Janus Kinase Inhibitors pharmacology, Acute Disease, Male, Myocardial Contraction drug effects, Nitriles pharmacology, Recombinant Proteins metabolism, Cells, Cultured, Pyrimidines pharmacology, Pyrazoles pharmacology, Phosphorylation, Mice, Protein Kinase Inhibitors pharmacology, Interleukin-11 metabolism, Interleukin-11 genetics, Myocytes, Cardiac metabolism, Myocytes, Cardiac drug effects, Myocytes, Cardiac pathology, Ventricular Function, Left drug effects, Mice, Knockout, Ventricular Dysfunction, Left physiopathology, Ventricular Dysfunction, Left metabolism, Ventricular Dysfunction, Left genetics, Ventricular Dysfunction, Left chemically induced, Ventricular Dysfunction, Left prevention & control, Signal Transduction, Disease Models, Animal, Mice, Inbred C57BL
- Abstract
Aims: Interleukin 11 (IL11) was initially thought important for platelet production, which led to recombinant IL11 being developed as a drug to treat thrombocytopenia. IL11 was later found to be redundant for haematopoiesis, and its use in patients is associated with unexplained and severe cardiac side effects. Here, we aim to identify, for the first time, direct cardiomyocyte toxicities associated with IL11, which was previously believed cardioprotective., Methods and Results: We injected recombinant mouse lL11 (rmIL11) into mice and studied its molecular effects in the heart using immunoblotting, qRT-PCR, bulk RNA-seq, single nuclei RNA-seq (snRNA-seq), and assay for transposase-accessible chromatin with sequencing (ATAC-seq). The physiological impact of IL11 was assessed by echocardiography in vivo and using cardiomyocyte contractility assays in vitro. To determine the activity of IL11 specifically in cardiomyocytes, we made two cardiomyocyte-specific Il11ra1 knockout (CMKO) mouse models using either AAV9-mediated and Tnnt2-restricted (vCMKO) or Myh6 (m6CMKO) Cre expression and an Il11ra1 floxed mouse strain. In pharmacologic studies, we studied the effects of JAK/STAT inhibition on rmIL11-induced cardiac toxicities. Injection of rmIL11 caused acute and dose-dependent impairment of left ventricular ejection fraction (saline: 62.4% ± 1.9; rmIL11: 32.6% ± 2.9, P < 0.001, n = 5). Following rmIL11 injection, myocardial STAT3 and JNK phosphorylation were increased and bulk RNA-seq revealed up-regulation of pro-inflammatory pathways (TNFα, NFκB, and JAK/STAT) and perturbed calcium handling. snRNA-seq showed rmIL11-induced expression of stress factors (Ankrd1, Ankrd23, Xirp2), activator protein-1 (AP-1) transcription factor genes, and Nppb in the cardiomyocyte compartment. Following rmIL11 injection, ATAC-seq identified the Ankrd1 and Nppb genes and loci enriched for stress-responsive, AP-1 transcription factor binding sites. Cardiomyocyte-specific effects were examined in vCMKO and m6CMKO mice, which were both protected from rmIL11-induced left ventricular impairment and molecular pathobiologies. In mechanistic studies, inhibition of JAK/STAT signalling with either ruxolitinib or tofacitinib prevented rmIL11-induced cardiac dysfunction., Conclusions: Injection of IL11 directly activates IL11RA/JAK/STAT3 in cardiomyocytes to cause acute heart failure. Our data overturn the earlier assumption that IL11 is cardioprotective and explain the serious cardiac side effects associated with IL11 therapy., Competing Interests: Conflict of interest: S.A.C. is a co-inventor on a number of patent applications relating to the role of IL11 in human diseases that include the published patents: WO2017103108, WO2017103108 A2, WO 2018/109174 A2, and WO 2018/109170 A2. S.A.C. is also a co-founder and shareholder of Enleofen Bio PTE LTD and VVB PTE LTD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.) more...
- Published
- 2024
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