title: MicroRNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1.
abstract: Diabetic cardiomyopathy is a common complication in patients with diabetes and is associated with underlying chronic inflammation and cardiac cell death, subsequently leading to heart failure (HF). ELAV-like protein 1 (ELAVL1) plays a critical role in the progression of inflammation and HF. However the role of ELAVL-1 in inflammation induced cardiac cell death (pyroptosis) under hyperglycemic condition remains elusive. Our data demonstrates that ELAVL1 expression augmented with a concomitant increase in caspase-1 and IL-1 beta expression in human hearts and human ventricular cardiomyocytes under hyperglycemic condition. Furthermore, ELAVL1 knockdown abrogates TNF-α induced canonical pyroptosis via NLRP3, caspase-1 and IL-1beta suppression. Bioinformatics analysis and target validation assays showed that miR-9 directly targets ELAVL1. Interestingly, miRNA-9 expression significantly reduced in high glucose treated cardiomyocytes and in human diabetic hearts. Inhibition of miR-9 upregulates ELAVL1 expression and activates caspase-1. Alternatively, treatment with miR-9 mimics attenuates hyperglycemia-induced ELAVL1 and inhibits cardiomyocyte pyroptosis. Taken together our study highlights the potential therapeutic implications of targeting miR-9/ELAVL1 in preventing cardiomyocyte cell loss during HF in diabetics.
authors.affiliation: Department of Cardiovascular Sciences, Centre for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Prince
authors.initials: P
authors.lastname: Jeyabal
authors.affiliation: Department of Cardiovascular Sciences, Centre for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Rajarajan A
authors.initials: RA
authors.lastname: Thandavarayan
authors.affiliation: Department of Cardiovascular Sciences, Centre for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Darukeshwara
authors.initials: D
authors.lastname: Joladarashi
authors.affiliation: Department of Cardiovascular Sciences, Centre for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Sahana
authors.initials: S
authors.lastname: Suresh Babu
authors.affiliation: Department of Cardiovascular Sciences, Centre for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Shashirekha
authors.initials: S
authors.lastname: Krishnamurthy
authors.affiliation: Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Bhimaraj
authors.affiliation: Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Youker
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.affiliation: Department of Cardiovascular Sciences, Centre for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA; Cell and Developmental Biology, Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, New York, NY, USA. Electronic address: pkrishnamurthy@houstonmethodist.org.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Krishnamurthy
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D058065:Diabetic Cardiomyopathies / Q000473:pathology; D000067780:ELAV-Like Protein 1 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000502:physiology; D000069292:Pyroptosis / Q000235:genetics*
chemical_list: D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs
keywords: Diabetic cardiomyopathy; ELAVL1; Inflammation; MicroRNA-9; Pyroptosis