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  • The following are the supplementary data


    The following are the supplementary data related to this article.
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    Acknowledgements We thank the other members of the Van Eck group for their practical support during the Resiniferatoxin experiments. We acknowledge the support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Arts and Sciences for the GENIUS project “Generating the best evidence-based pharmaceutical targets for atherosclerosis” [CVON2011-19]. This study was supported by the Netherlands Organization for Scientific Research [VICI Grant 91813603]. Miranda Van Eck is an Established Investigator of the Netherlands Heart Foundation [Grant 2007T056].
    Introduction Pathological cardiac hypertrophy, one of the most critical risk factors for the progression of Resiniferatoxin failure, can be attributed to long-term hypertrophic stress, such as hypertension, ischemia, myocarditis, and valvular disease [1,2]. Under normal physiological conditions, cardiac hypertrophy maintains heart function efficiently. However, persistent hypertrophy causes the deposition of extracellular collagen, the loss of adrenergic responsivity, and metabolic changes [3]. Together, these alterations result in cell apoptosis and irreversible cardiac structural remodeling, which ultimately leads to heart failure and sudden death [[3], [4], [5]]. Numerous studies have demonstrated various specific peptide hormones, growth factors, and cytokines with cardioprotective function. Phosphoinositide 3-kinase (PI3K) and its downstream serine-threonine kinase, AKT (or Protein Kinase B) exerts cardioprotective effects in cardiac hypertrophy models [4,6]. Our previous study identified that the loss of inducible IkB kinase (IKKi/IKKe), a recently reported serine-threonine IKK-related kinase, which could activate AKT independent of PI3K [7], aggravated aortic banding-induced cardiac hypertrophy through activating the AKT and NF-κB signaling pathways [8]. In cultured cells, IKKi overexpression also suppressed the AKT and NF-kB signaling pathways [6]. Developing a deeper understanding of the regulation of IKKi signaling may provide novel strategies for the treatment of pathological cardiac hypertrophy and heart failure. Of the mammalian genome, protein-coding genes take up about 1.5%, while non-coding RNAs (ncRNAs) account for more substantial genomic parts [9]. The ncRNAs have a beneficial effect in sustaining the normal physiological functions of cells [[10], [11], [12]]. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) both are a crucial constituent part of ncRNAs. Numerous miRNAs have been indicated to affect heart hypertrophy, such as miR-1, miR-133, and miR-214 [[13], [14], [15]]. In addition, lncRNAs have been reported play critical regulatory roles in cardiovascular disease, particularly in heart hypertrophy [[16], [17], [18], [19], [20]]. Regarding the molecular mechanism, the competitive endogenous RNAs (ceRNA), containing shared microRNA response elements (MREs), could bind to microRNA efficiently. Therefore, the existence of ceRNA will affect the activity of microRNAs [21]. Salmena et al. speculated that these ceRNAs, including protein-coding genes, pseudogenes, and long non-coding RNAs, could interact with each other to form a ceRNA network with their ability of binding to microRNA [22]. The communication forms extensive cis and trans-regulatory crosstalk throughout the transcriptome. However, how the ceRNA network participates in the progression of cardiac hypertrophy needs further elucidation. During the present exploration, based on GEO database (GSE60291), we identified dysregulated lncRNAs in human cardiac hypertrophy and selected lncRNA cytoskeleton regulator RNA (CYTOR) due to its high expression and positive correlation with IKBKE. Next, the detailed functions of CYTOR knockdown on heart hypertrophy in vivo and in vitro were examined. By performing KEGG and Mirpath annotation, miRNAs related to hypertrophic cardiomyopathy (HCM, hsa05410) were identified, and miR-155 was selected because of its role in hypertrophic cardiomyopathy [23]. The predicted interactions of CYTOR, miR-155 and IKBKE were validated, and the dynamic effect of CYTOR/miR-155 axis on hypertrophic cardiomyopathy and downstream IKKi and NF-κB signaling pathway was illustrated.