Rad regulation of CaV1.2 channels controls cardiac fight-or-flight response

Papa, Arianne; Zakharov, Sergey I.; Katchman, Alexander N.; Kushner, Jared; Chen, Bi-Xing; Yang, Lin; Liu, Guoxia; Jimenez, Alejandro Sanchez; Eisert, Robyn J.; Bradshaw, Gary A.; Dun, Wen; Ali, Shah Raj; Rodriques, Aaron; Zhou, Karen Zhuqian; Topkara, V.K.; Yang, Mei; Morrow, John; Tsai, Emily J.; Karlin, Arthur; Wan, Elaine; Kalocsay, Marian; Pitt, Geoffrey S.; Colecraft, Henry M.; Ben-Johny, Manu; Marx, Steven O.

doi:10.1038/s44161-022-00157-y

Cited by 26 publications

(23 citation statements)

References 63 publications

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“…Emission was detected at 510 nm through a Nikon Fluor ×10 objective by a Prime BSI-Express sCMOS (scientific Complementary Metal–Oxide–Semiconductor) camera (Teledyne Photometrics) and Nikon Elements (Version 5.21) as previously described. 57 Cells were randomly selected for rhythmicity analysis. Calcium fluorescence was analyzed using a written Python code available on Github.…”

Section: Methodsmentioning

confidence: 99%

Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery

Wang¹,

Nash²,

Rao³

et al. 2023

Cell Reports Medicine

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Section: Methodsmentioning

confidence: 99%

Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery

Wang¹,

Nash²,

Rao³

et al. 2023

Cell Reports Medicine

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“…On closer inspection, the L-type calcium channel inhibitor Rrad was identified as one of the most significantly upregulated genes at 1 hour (Fc:4.91, FDR:3.2e-8) and 3 hours (Fc:4.51, FDR:9.2e-9) post rmIL11 treatment [Fig2A, B]. The Rrad protein product RAD-GTPase is a well-characterised and potent inhibitor of calcium current through L-type calcium channels 24,25 and its acute upregulation may account for the changes in calcium transients seen in isolated CM preparations.…”

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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“…Its pharmacological blockade was observed to reduce the rate of activation of sinoatrial cells [126][127][128]. The channels carrying the current were long thought to be phosphorylated directly by PKA, but recent studies demonstrated that the cAMP-dependent activation of the current is in fact mediated by Rad, a channel inhibitor associated with the local signalosome [129][130][131]. The regulatory sequence therefore involves cAMP activation of PKA, phosphorylation of Rad molecules in the vicinity and consequent release of its inhibitory action on L-type calcium current, which is enhanced.…”

Section: Camp and Membrane Clockmentioning

confidence: 99%

Compartmentalized cAMP signalling and control of cardiac rhythm

Tomek

Zaccolo

2023

Phil. Trans. R. Soc. B

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In the last 30 years, the field of cyclic adenosine 3′,5′-monophosphate (cAMP) signalling has witnessed a transformative development with the realization that cAMP is compartmentalized and that spatial regulation of cAMP is critical for faithful signal propagation and hormonal specificity. This recognition has changed our understanding of cAMP signalling from the canonical model, where a linear pathway connects a plasma membrane receptor to intracellular effectors and their targets, to a model where signal transduction occurs within a complex network of alternative branches and where an individual receptor leads to activation of a limited fraction of the network, enabled by local regulation of independent signalling units, resulting in a specific functional outcome. The cardiac myocyte has served as the cell model for many of the original findings leading to this paradigm. In this review, we cover some of the evidence supporting this new perspective and discuss how this model is providing novel mechanistic insight into cardiac myocyte physiology. With a focus on the regulation of cardiac rhythm, we consider how this model can provide an original framework for the identification of disease mechanisms. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

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Rad regulation of CaV1.2 channels controls cardiac fight-or-flight response

Cited by 26 publications

References 63 publications

Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery

Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery

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

Compartmentalized cAMP signalling and control of cardiac rhythm

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