Activation of the mammalian target of rapamycin signaling pathway underlies a novel inhibitory role of ring finger protein 182 in ventricular remodeling after myocardial ischemia‐reperfusion injury

Abstract

Myocardial ischemia‐reperfusion injury (MIRI) is a major cause of cardiovascular disease, leading to mortality and disability associated with coronary occlusion worldwide. A correlation of mammalian target of rapamycin (mTOR)/nuclear factor‐kappa B (NF‐κB) signaling pathway has been observed with brain damage resulting from myocardial ischemia. Therefore, by establishing MIRI rat model, this study aimed to explore whether ring finger protein 182 (RNF182) regulates the mTOR signaling pathway affecting MIRI. Initially, MIRI rat model was successfully established, followed by either treatment of shRNF182 or phosphoesterase (PITE) (inhibitor of the mTOR signaling pathway). Then, the serum levels of superoxide dismutase (SOD), glutathione peroxidase (GSH‐Px) and malondialdehyde (MDA), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP), and left ventricular end‐diastolic pressure (LVEDP) were determined, followed by detection of myocardial infarct sizes and myocardial cell apoptosis. Moreover, the levels of related genes/proteins were determined to further determine the mechanisms of RNF182 in MIRI. First, RNF182 was upregulated in MIRI. Another key observation of this study was that rats with shRNF182 presented with downregulated SOD, GSH‐Px, and MDA in serum, accompanied by decreased levels of LVEF, LVFS, LVSP, and LVEDP. In addition, both reduced myocardial infarct sizes and apoptosis of myocardial cells were observed after silencing RNF182. Furthermore, silencing of the RNF182 was observed to downregulate Bcl 2–associated X and cysteine proteinase 3 but upregulate mTOR, ribosome protein subunit 6 kinase 1, eukaryotic elongation factor 2, and B‐cell lymphoma‐2. Importantly, the effects of RNF182 silencing were reversed after PITE treatment. In conclusion, our study demonstrates that RNF182 silencing can prevent ventricular remodeling in rats after MIRI by activating the mTOR signaling pathway.

RNF183 Is a Prognostic Biomarker and Correlates With Tumor Purity, Immune Infiltrates in Uterine Corpus Endometrial Carcinoma

“…RNF183, RNF182, RNF186, and RNF152, are further identified as the RNF183 family, which share the similar structure RING finger domain (C3HC4) at their N-terminus and transmembrane domains at their C-terminus with high homology (Kaneko et al, 2016;Okamoto et al, 2020a). As common features, members of RNF183 family have exhibited a broad range of functions in diverse biological and pathological processes such as prolonged endoplasmic reticulum stress, apoptosis, ischemia-reperfusion injury, oxygen, and glucose metabolism, immune and inflammatory response (Liu et al, 2008;Nectoux et al, 2010;Wang et al, 2018;Wu et al, 2018;Cao et al, 2019;Maeoka et al, 2019a). It was proposed that RNF183 could be as one of the potential biomarkers for endometrial cancer through gene expression screening (Colas et al, 2011).…”

The E3 ubiquitin ligase RNF182 inhibits TLR‐triggered cytokine production through promoting p65 ubiquitination and degradation

“…RNF182 is upregulated in AD brains and neuronal cells exposed to injurious insults, and then may cause impaired gap junction complexes by affecting ATP6V0C expression [17]. In another MIRI model, RNF182 was also observed to be upregulated and harmful to ventricular remodeling in rats [18]. The above two studies suggest that RNF182 can be upregulated in inflammation and also have a possible role in inflammation.…”

“…The E3 ligase RNF182 has been reported to participate in Alzheimer's disease (AD) and myocardial ischemia–reperfusion injury (MIRI) , which have a close relationship with the immune response. RNF182 is upregulated in AD brains and neuronal cells exposed to injurious insults, and then may cause impaired gap junction complexes by affecting ATP6V0C expression .…”

The Role of Tissue-Specific Ubiquitin Ligases, RNF183, RNF186, RNF182 and RNF152, in Disease and Biological Function

“…Although RNF182 appears to be specifically expressed in the nervous system, its expression and function in other tissues were reported. Rnf182 was also shown to be upregulated in a rat model of myocardial ischemia-reperfusion injury (MIRI) [37]. Its silencing by shRNA was shown to reduce myocardial infarct size and myocardial cell apoptosis in this rat model.…”

“…K63 [18,19] Ubc5c (in vitro) [11]; UbcH5c (in vitro) [12] IBD [17,18]; endometrial carcinoma [22]; colorectal cancer [15,16,20]; Ewing Sarcoma [21] RNF186 ER [23]; lysosome? [24] lower gastrointestinal tract, kidney [10] BNip1 [23]; Occludin [25]; Sestrin-2 [24] apoptosis [23,26]; mTORC1 [24] K29 [23]; K48 [24,25]; K63 [23,24] IBD [25,[27][28][29][30][31][32][33]; CKD [34] RNF182 lysosome [35] nervous system (cortex, hippocampus, cerebellum, spinal cord) [10,35] oxygen and glucose deprivation [35]; MeCP2 mutation [36]; ischemia-reperfusion injury [37]; TLR stimuli [38] ATP6V0C [35]; NF-κB p65 subunit [38] apoptosis [35]; mTORC1 [37]; NF-κB [38] K48 [35,…”