MicroRNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1

• Published in: Biochemical and biophysical research communications 2016-03, Vol.471 (4), p.423-429
• Main Authors: Jeyabal, Prince, Thandavarayan, Rajarajan A., Joladarashi, Darukeshwara, Suresh Babu, Sahana, Krishnamurthy, Shashirekha, Bhimaraj, Arvind, Youker, Keith A., Kishore, Raj, Krishnamurthy, Prasanna
• Format: Article
• Language: English
• Subjects: Animals; bioinformatics; cardiomyocytes; cardiomyopathy; caspase-1; cell death; Cell Line; Cells, Cultured; diabetes; Diabetic Cardiomyopathies - pathology; Diabetic cardiomyopathy; ELAV-Like Protein 1 - genetics; ELAV-Like Protein 1 - metabolism; ELAVL1; Gene Expression Regulation; Gene Knockdown Techniques; glucose; heart failure; Heart Ventricles - pathology; Humans; hyperglycemia; Hyperglycemia - genetics; Hyperglycemia - metabolism; Inflammation; interleukin-1beta; Mice; MicroRNA-9; MicroRNAs - genetics; MicroRNAs - metabolism; Myocytes, Cardiac - pathology; Myocytes, Cardiac - physiology; patients; Pyroptosis; Pyroptosis - genetics; tumor necrosis factor-alpha
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.02.065

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. Schematic representation that illustrate high glucose induced cardiac pyroptosis and regulatory role of ELAVL1 and miR-9. [Display omitted] •Human diabetic heart shows increased ELAVL1, pyroptosis and decreased miR-9.•Human cardiomyocytes exposed to HG show similar changes.•KD of ELAVL1 impairs canonical inflammatory pathway associated pyroptosis.•miR-9 directly targets ELAVL1.•miR-9 mimic transfection or ELAVL1 knockdown inhibits pyroptosis.