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 hyper glycemic 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.

Pioglitazone Confers Neuroprotection Against Ischemia-Induced Pyroptosis due to its Inhibitory Effects on HMGB-1/RAGE and Rac1/ROS Pathway by Activating PPAR-ɤ

“…Therefore, caspase-1 dependence is a definitive feature of pyroptosis that is characterized by the release of pro-inflammatory contents and plasma membrane rupture. Recent studies have demonstrated that pyroptosis mediated the death of renal and cardiac cells, leading to kidney and heart failure [11, 12, 43]. Our findings were consistent with those previously reported results.…”

MicroRNA-9 Inhibits NLRP3 Inflammasome Activation in Human Atherosclerosis Inflammation Cell Models through the JAK1/STAT Signaling Pathway

“…MiR-9 has been reported to play important roles in inflammatory response [36], immune regulation [36], lipid uptake [38], neuron differentiation [39], and many kinds of tumors [40]. Our results indicate potential anti-inflammatory effects and inhibition of NLRP3 inflammasome by mir-9.…”

“…Through regulating its target gene ELAVL1 , mir-9 inhibited hyperglycemia-induced pyroptosis (cardiac cell death) in human ventricular cardiomyocytes. ELAVL1 knockdown abrogates TNF-α induced canonical pyroptosis via NLRP3, caspase-1 and IL-1β suppression[40]. Over-expression of miR-9 in isolated human chondrocytes reduced IL-1β-induced TNF-α production and inhibited MMP-13 in human chondrocytes[41].…”

“…NF-κB1 was previously shown to be one of mir-9’s target genes. MiR-9 inhibits melanoma cell proliferation and migration through down-regulation of the NF-κB1-Snail1 pathway [40]. So it is possible for mir-9 to inhibit its downstream NF-κB signal transduction pathway through regulating JAK1.…”

A New Participant in the Pathogenesis of Alcoholic Gastritis: Pyroptosis

“…Caspase-11 can trigger pyroptosis, but its effects on IL-1β and IL-18 maturation are indirect, because this process requires the NLRP3-dependent activation of caspase-1 [26,27]. Pyroptosis induces pathological inflammation, which is involved in the pathogenesis of multiple inflammatory diseases in several organs, including bowel [28], brain [29], heart [30] and kidney [31]. In gastritis, inflammation and mucosal cell death are also present.…”