miR-214-3p Attenuates Sepsis-Induced Myocardial Dysfunction in Mice by Inhibiting Autophagy through PTEN/AKT/mTOR Pathway

Abstract

<jats:p><jats:italic>Aims</jats:italic>. More than half of the patients with sepsis would develop cardiac dysfunction, which is termed as sepsis-induced myocardial dysfunction (SIMD). Previous studies suggest that autophagy may play an important role in SIMD. The present study investigated whether miR-214-3p could attenuate SIMD by inhibiting autophagy. <jats:italic>Main Methods</jats:italic>. In this article, we investigated the role of autophagy in a mouse model of cecal ligation and puncture (CLP). The structure and function of hearts harvested from the mice were evaluated. Myocardial autophagy levels were detected with immunohistochemical, immunofluorescent, and Western blot. <jats:italic>Key Findings</jats:italic>. miR-214-3p can alleviate SIMD in septic mice by inhibiting the level of cardiac autophagy to attenuate myocardial dysfunction. Moreover, this study showed that miR-214-3p inhibited autophagy by silencing PTEN expression in the myocardial tissues of septic mice. <jats:italic>Significance</jats:italic>. This study showed that miR-214-3p attenuated SIMD through myocardial autophagy inhibition by silencing PTEN expression and activating the AKT/mTOR pathway. The present findings supported that miR-214-3p may be a potential therapeutic target for SIMD.</jats:p>

MicroRNAs and Sepsis-Induced Cardiac Dysfunction: A Systematic Review

“…In their study, myocardial inflammation, apoptosis, and dysfunction were decreased when the miR-214 expression was enhanced via its precursor, and, vice versa, they were worsened by its inhibitor. In a different study, it was demonstrated that miR-214-3p inhibits autophagy via the PTEN/AKT/mTOR pathway [ 53 ].…”

“…It is a phosphatase that regulates various cellular signaling pathways and has tumor suppression properties. Some of the aforementioned studies demonstrated that PTEN is targeted by miRNAs in sepsis-induced cardiac damage [ 53 , 59 , 60 ]. A further complication in understanding the role of miRNAs in septic myocardial injury is represented by lncRNAs, as evidenced by some research studies mentioned above [ 45 , 73 , 74 ].…”

“…Ge et al 2018 [52] MiR-214-3p Sang et al 2020 [53] MiR-218a-5p ↑ -Zhang et al [69] MiR-219a-1-3p ↑ -Zhang et al [69] MiR-223-5p ↓ Sema3A Wang et al 2014 [32] MiR-233-3p ↑ -Zhang et al [69] MiR-233-5p ↑ -Zhang et al [69] MiR-322-5p ↓ -Zhang et al [69] MiR-328 ↑ its inhibition is protective -Sun et al 2020 [68] MiR-330-5p ↑ -Zhang et al [69] ↓ its up-regulation is protective TRAF6 Xing et al 2020 [74] MiR-339-3p ↑ -Zhang et al [69] MiR-340-3p ↑ -Zhang et al [69] MiR-362-5p ↓ -Zhang et al [69] MiR-369-5p ↑ -Zhang et al [69] MiR-378a-5p ↓ -Zhang et al [69] MiR-379-5p ↑ -Zhang et al [69] MiR-380-3p ↑ -Zhang et al [69] MiR-409a-3p ↑ -Zhang et al [69] MiR-425-3p ↓ -Zhang et al [69] MiR-434-5p ↑ -Zhang et al [69] MiR-466b-5p ↑ -Zhang et al [69] MiR-490-5p ↑ -Zhang et al [69] MiR indicates microRNA; HSPA4, the heat shock protein previously known as hsp70; SORBS2, sorbin and SH3 domain containing 2; TGIF1, 5 TG3 -interacting factor 1; PTEN, phosphatase and tensin homolog; TRAF6, tumor necrosis factor receptor-associated factor 6; IκκB, inhibitor of nuclear factor kappa-B kinase subunit beta; XIAP, X-chromosome-linked inhibitor of apoptosis; Nrf2, nuclear factor (erythroid-derived 2)-like 2; SIRT1, sirtuin 1; TRL4, toll-like receptor 4; HMGA2, high mobility group at-hook 2; STX2, syntaxin-2; IRAK1, interleukin-1 receptor-associated kinase 1; ErbB4, erb-B2 receptor tyrosine kinase 4; Akt2, serine/threonine kinase 2; Pea15a, phosphoprotein enriched in astrocytes; Arrb2, β-arrestin 2; SOCS2, suppressor of cytokine signaling 2; Sema3A, semaphorin3A; AQP1, aquaporin 1.…”

Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish

“…The exact molecular mechanism by which LARS mutation influences human ILFS1 needs to be determined using knock-in animal models, wherein a corresponding mutation is introduced into the zebrafish larsb locus. Moreover, there is increasing evidence for autophagy being associated with many diseases, including sepsis, Parkinson's disease, and Alzheimer's disease 40 – 42 . Hence, autophagy regulation by LARS may lead to new therapeutics for these related disorders.…”

Leucyl-tRNA Synthetase Deficiency Systemically Induces Excessive Autophagy in Zebrafish

“…The exact molecular mechanism by which LARS mutation influences human ILFS1 needs to be determined using knock-in animal models, wherein a corresponding mutation is introduced into the zebrafish larsb locus. Moreover, there is increasing evidence for autophagy being associated with many diseases, including sepsis, Parkinson's disease, and Alzheimer's disease [29][30][31] . Hence, autophagy regulation by LARS may lead to new therapeutics for these related disorders.…”