Cardiac ankyrin repeat protein contributes to dilated cardiomyopathy and heart failure

Zhang, Na; Ye, Feiming; Zhou, Yu; Zhu, Wei; Xie, Cuiping; Zheng, Haiqiong; Chen, Han; Chen, Jinghai; Xie, Xing

doi:10.1096/fj.201902802rr

Cited by 4 publications

(4 citation statements)

References 44 publications

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“…Left ventricle internal diameters at end-diastole and end-systole (LVIDd and LVIDs, respectively) were measured. The LV ejection fraction (EF), fractional shortening (FS), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV) were analyzed independently by three investigators who were blinded to the experimental design ( 27 ).…”

Section: Methodsmentioning

confidence: 99%

Lipocalin-2 in neutrophils induces ferroptosis in septic cardiac dysfunction via increasing labile iron pool of cardiomyocytes

Huang

Zhang

Xie

et al. 2022

Front. Cardiovasc. Med.

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Cardiac dysfunction is a common complication of sepsis with high mortality. The present study was designed to identify the effect of neutrophil-derived lipocalin-2 (LCN2) in septic cardiac dysfunction (SCD) and its potential mechanism. Wild-type (WT) and LCN2-knockout (LCN2 KO) mice were peritoneally injected with lipopolysaccharide (LPS) to induce SCD. The cardiac function was assessed 12 h after LPS injection by echocardiography. Cardiac tissue was harvested for the evaluation of malonaldehyde (MDA) and prostaglandin E synthase 2 (PTGS2) mRNA levels. LPS induced ferroptosis and SCD in mice. LCN2 deficiency attenuated cardiac injury post-LPS administration. In vitro, LCN2 expression in neutrophils increased in response to LPS. Ferroptosis of cardiomyocytes induced by conditioned medium (CM) from LPS-induced neutrophils of WT mice could be attenuated in CM from LPS-induced neutrophils of LCN2 KO mice. Exogenous LCN2 induced H9C2 cell ferroptosis via increasing labile iron pool (LIP). In conclusion, our results showed that LCN2 deficiency prevented heart dysfunction and ferroptosis in SCD mice and suggested that neutrophil-derived LCN2 might be a promising therapeutic target for SCD.

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Section: Methodsmentioning

confidence: 99%

Lipocalin-2 in neutrophils induces ferroptosis in septic cardiac dysfunction via increasing labile iron pool of cardiomyocytes

Huang

Zhang

Xie

et al. 2022

Front. Cardiovasc. Med.

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“…This state is defined by the expression of cardiomyocyte stress factors including Ankrd1 , Ankrd23 and Xirp2 [Figure 3E & Suppl Fig S4B] . Ankrd1 and Ankrd23 are stress-inducible ankyrin repeat proteins which are elevated in dilated cardiomyopathies 26,27 . Xirp2 encodes cardiomyopathy-associated protein 3 and is upregulated in CMs in response to stress 28,29 .…”

Section: Resultsmentioning

confidence: 99%

Interleukin 11 therapy causes acute heart failure and its use in patients should be reconsidered

Sweeney,

O’Fee,

Villanueva-Hayes

et al. 2023

Preprint

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BackgroundInterleukin 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 cardiac side effects. Here we identify previously unappreciated and direct cardiomyocyte toxicities associated with IL11 therapy.MethodsWe 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 ATAC-seq. The physiological impact of IL11 was assessed by echocardiographyin vivoand using cardiomyocyte contractility assaysin vitro. To determine the activity of IL11 specifically in cardiomyocytes we made two cardiomyocyte-specificIl11ra1knockout mouse models using either AAV9-mediated andTnnt2-restricted (vCMKO) orMyh6(m6CMKO) Cre expression and anIl11ra1floxed mouse strain. In pharmacologic studies, we studied the effects of JAK/STAT inhibition on rmIL11-induced cardiac toxicities.ResultsInjection of rmIL11 caused acute and dose-dependent impairment of left ventricular ejection fraction (saline (2 µL/kg), 60.4%±3.1; rmIL11 (200 mcg/kg), 31.6%±2.0; p<0.0001, n=5). Following rmIL11 injection, myocardial STAT3 and JNK phosphorylation were increased and bulk RNA-seq revealed upregulation 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 andNppbin the cardiomyocyte compartment. Following rmIL11 injection, ATAC-seq identified epigenetic enrichment of theAnkrd1andNppbgenes and 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.ConclusionsInjection of IL11 directly activates 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, which questions its continued use in patients.Clinical PerspectiveWhat is new?Injection of IL11 to mice causes acute and dose-dependent left ventricular impairmentIL11 activates JAK/STAT3 in cardiomyocytes to cause cell stress, inflammation and impaired calcium handlingThese data identify, for the first time, that IL11 is directly toxic in cardiomyocytes, overturning the earlier literature that suggested the oppositeWhat are the clinical implications?Recombinant human IL11 (rhIL11) is used as a drug to increase platelets in patients with thrombocytopenia but this has severe and unexplained cardiac side effectsWe show that IL11 injection causes cardiomyocyte dysfunction and heart failure, which explains its cardiac toxicities that were previously thought non-specificThese findings have immediate translational implications as they question the continued use of rhIL11 in patients around the world

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“…[29][30][31] Furthermore, it has been shown that downregulation of CARP expression induces upregulation of ryanodine receptor 2 expression, resulting in slow and continuous entry of Ca 2+ into the cytoplasm. 32 In addition, 2 (CASQ2) is the major Ca 2 +-binding protein on the sarcoplasmic reticulum and the primary Ca 2+ reservoir for the myocardium. Myocardial CARP specifically binds and interacts with specific CASQ2 domains through the CasQ-binding sequence.…”

Section: Discussionmentioning

confidence: 99%

Potential biomarker of acute anthracycline-induced cardiotoxicity among children with acute lymphoblastic leukemia: cardiac adriamycin-responsive protein

Li,

Tian,

Huang

et al. 2023

Journal of Cardiovascular Pharmacology

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This study aimed to investigate whether serum cardiac adriamycin-responsive protein (CARP) can serve as a sensitive and specific biomarker of Anthracyclines (ANT)-induced cardiotoxicity. Fifty-five children with acute lymphoblastic leukemia (ALL) were recruited. Before and after the administration of ANT, serum levels of CARP, high-sensitivity troponin T (TNT-HS), Creatine Kinase-MB (CK-MB), and electrocardiogram were measured. post-chemotherapeutic clinical manifestations of cardiotoxicity were also investigated. Adverse cardiac events (ACEs) were graded according to the Common Terminology Criteria for Adverse Events(CTC AE) 4.0. Then, the CARP expression was statistically analyzed among different groups. The receiver operating characteristic (ROC) curve was used to evaluate the efficacy of CARP in predicting acute ANT-induced cardiotoxicity. After ANT chemotherapy, the serum CARP concentration increased in the NACEs (Non-ACEs) group but decreased in the ACEs group (P<0.05). In addition, Not only the serum CARP levels (△CARP) was negatively correlated with the grade of ACEs (R=-0.754, P<0.0001) but also the extent of QTc prolongation (△QTc; R=-0.5592, P<0.01). The area under the ROC curve of CARP was 90.94% (P<0.0001), and the sensitivity and specificity were 88.64% and 91.67%, respectively, all of which are superior to △TNT-HS, △CK-MB, and △QTc. In conclusion, Serum CARP could serve as a novel sensitive and specific biomarker of acute ANT-induced cardiotoxicity, which is negatively associated with ACE grade.

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Cardiac ankyrin repeat protein contributes to dilated cardiomyopathy and heart failure

Cited by 4 publications

References 44 publications

Lipocalin-2 in neutrophils induces ferroptosis in septic cardiac dysfunction via increasing labile iron pool of cardiomyocytes

Lipocalin-2 in neutrophils induces ferroptosis in septic cardiac dysfunction via increasing labile iron pool of cardiomyocytes

Interleukin 11 therapy causes acute heart failure and its use in patients should be reconsidered

Potential biomarker of acute anthracycline-induced cardiotoxicity among children with acute lymphoblastic leukemia: cardiac adriamycin-responsive protein

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