Dexmedetomidine inhibits pyroptosis by down-regulating miR-29b in myocardial ischemia reperfusion injury in rats.

Dexmedetomidine (DEX) was reported to protect heart against ischemic-reperfusion (IR) but the mechanism herein remains elusive. This study aims to explore the mechanism of DEX on pyroptosis induced by myocardial ischemic reperfusion (MIR). MIR rat models were established and injected DEX or miR-29b agomir/antagomir separately. The possible effect of DEX or miR-29b on myocardial cells was assessed according to measurement on creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), interleukin-1β (IL-1β) and interleukin-18 (IL-18), myocardial infarction size, myocardial injury and apoptosis. Western blot determined the expression levels of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC) and cleaved-caspase-1. Hypoxia/reoxygenation (H/R) cell model was established. The lactate dehydrogenase (LDH) content released by myocardial cells was examined. The relation between miR-29b and FoxO3a was confirmed by dual luciferase reporter gene assay. FoxO3a or ARC level was elevated in H/R myocardial cells to detect its effect on pyroptosis. MIR rat models were successfully established, in which cell pyroptosis was triggered as evidenced by increased expression levels of NLRP3, ASC and cleaved-caspase-1. Rats with DEX precondition had attenuated cell pyroptosis and ameliorated inflammatory response. FoxO3a was a target of miR-29b. MiR-29b agomir or miR-29b antagomir could inhibit or promote the protective effect of DEX on MIR. Overexpression of FoxO3a/ARC axis could suppress myocardial pyroptosis induced by H/R. DEX could ameliorate MIR injury (MIRI) and H/R injury in rats and inhibit H/R induced pyroptosis in myocardial cells via down-regulating miR-29b to activate FoxO3a/ARC axis.

Zhong Y ，Li YP ，Yin YQ ，Hu BL ，Gao H ... -  《-》

Dexmedetomidine abates myocardial ischemia reperfusion injury through inhibition of pyroptosis via regulation of miR-665/MEF2D/Nrf2 axis.

Wang L ，Liu J ，Wang Z ，Qian X ，Zhao Y ，Wang Q ，Dai N ，Xie Y ，Zeng W ，Yang W ，Bai X ，Yang Y ，Qian J ... -  《-》

Sevoflurane exerts protection against myocardial ischemia-reperfusion injury and pyroptosis through the circular RNA PAN3/microRNA-29b-3p/stromal cell-derived factor 4 axis.

Sevoflurane is suggested to exert protective functions against myocardial ischemia-reperfusion injury (MIRI). However, the particular mechanism remains elusive. Therefore, this research explored the mechanism of sevoflurane in MIRI-induced damage and pyroptosis. Subsequent to gain-or loss-of-function assays or/and sevoflurane treatment, the MIRI model was developed in rats. Cardiac function and body and heart weight of rats were evaluated, followed by measurement of apoptosis and creatine kinase MB (CK-MB), lactate dehydrogenase (LDH), and pyroptosis-related protein levels. After loss-of-function assays or/and sevoflurane treatment in human cardiomyocytes (HCMs), the hypoxia/reoxygenation (H/R) model was constructed. In HCMs, cell viability, apoptosis, and pyroptosis-related proteins were detected. Circular RNA PAN3 (circPAN3), microRNA (miR)-29b-3p, and stromal cell-derived factor 4 (SDF4) expression was determined in rat myocardial tissues and HCMs. Mechanistically, interactions among circPAN3, miR-29b-3p, and SDF4 were analyzed. MIRI modeling increased miR-29b-3p expression and diminished circPAN3 and SDF4 expression in H/R-treated HCMs and MIRI rats, which was nullified by sevoflurane preconditioning. Mechanistically, circPAN3 negatively targeted miR-29b-3p to upregulate SDF4. Moreover, sevoflurane preconditioning reduced heart weight/body weight ratio, LDH, CK-MB, myocardial infarct size, left ventricular end-diastolic pressure, apoptosis, and pyroptosis, while elevating the increase and decrease of left ventricular pressure (±dp/dt max) and left ventricular systolic pressure in MIRI rats. In addition, sevoflurane preconditioning augmented viability while diminishing apoptosis and pyroptosis in H/R-treated HCMs. Moreover, circPAN3 silencing or miR-29b-3p overexpression abrogated alleviatory effects of sevoflurane on myocardial injury and pyroptosis in vitro. Sevoflurane treatment ameliorated myocardial injury and pyroptosis in MIRI via circPAN3/miR-29b-3p/SDF4 axis.

An L ，Zhong Y ，Tan J ，Liu Y ，Li A ，Yang T ，Wang S ，Liu Y ，Gao H ... -  《-》

MiR-155 is Involved in Renal Ischemia-Reperfusion Injury via Direct Targeting of FoxO3a and Regulating Renal Tubular Cell Pyroptosis.

Ischemia/reperfusion injury (IRI) plays a crucial role in renal transplantation and can cause renal failure associated with pyroptosis, a pro-inflammatory-induced programmed cell death. Small endogenous non-coding RNAs have been shown to be involved in renal ischemia/reperfusion injury. This study was performed to investigate which miRNAs regulate pyroptosis in response to renal ischemia/reperfusion injury and determine the mechanism underlying this regulation. An in vivo rat model of renal IRI was established, and the serum and kidneys were harvested 24 h after reperfusion to assess renal function and histological changes. For the in vitro study, the cultured human renal proximal tubular cell line HK-2 was subjected to 24 h of hypoxia (5% CO2, 1% O2, and 94% N2) followed by 12 h of reoxygenation (5% CO2, 21% O2, and 74% N2). The mRNA expression levels were analyzed by real-time PCR, and the protein expression levels were analyzed using Western blot, immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). Bioinformatics analyses were applied to predict miR-155 targets, which were then confirmed by a luciferase reporter assay. We found that the levels of pyroptosis-related proteins, including caspase-1, caspase-11, IL-1β and IL-18, were significantly increased after renal ischemia/reperfusion injury. Similarly, hypoxia-reoxygenation injury (HRI) also induced pyroptosis in HK2 cells. Furthermore, our study revealed that miR-155 expression was substantially increased in the renal tissues of IRI rats and in HRI HK2 cells. Up-regulation of miR-155 promoted HK2 cell pyroptosis in HRI; conversely, knockdown of miR-155 attenuated this process. To understand the signaling mechanisms underlying the pro-pyroptotic activity of miR-155, we found that exogenous expression of miR-155 up-regulated the expression of caspase-1 as well as the pro-inflammatory cytokines IL-1β and IL-18. Moreover, miR-155 directly repressed FoxO3a expression and its downstream protein apoptosis repressor with caspase recruitment domain (ARC). Our study proposes a new signaling pathway of miR-155/FoxO3a/ARC leading to renal pyroptosis under ischemia/reperfusion injury conditions.

Wu H ，Huang T ，Ying L ，Han C ，Li D ，Xu Y ，Zhang M ，Mou S ，Dong Z ... -  《-》

Overexpression of lncRNA HULC Attenuates Myocardial Ischemia/reperfusion Injury in Rat Models and Apoptosis of Hypoxia/reoxygenation Cardiomyocytes via Targeting miR-377-5p through NLRP3/Caspase‑1/IL‑1β Signaling Pathway Inhibition.

Liang H ，Li F ，Li H ，Wang R ，Du M ... -  《-》