Pyroptosis and ferroptosis induced by mixed lineage kinase 3 (MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload

Wang, Junyan; Deng, Bo; Liu, Qing; Huang, Yu‐Sheng; Chen, Weitao; Li, Jing; Zhou, Zheng; Zhang, Lu; Liang, Birong; He, Jiaming; Chen, Zixin; Cui, Yan; Yang, Zhong-Qi; Xian, Shaoxiang; Wang, Lingjun

doi:10.1038/s41419-020-02777-3

Cited by 150 publications

(81 citation statements)

References 76 publications

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“…Sham-operated mice underwent a thoracotomy procedure without the constriction of the aorta. In the TAC group, we used a 6–0 silk suture ligature to constrict transverse aorta against a blunted 27-gauge needle to yield a narrowing to 25–30% of its original cross-sectional area 38 .…”

Section: Methodsmentioning

confidence: 99%

Knockout RAGE alleviates cardiac fibrosis through repressing endothelial-to-mesenchymal transition (EndMT) mediated by autophagy

Zhang

Wang

et al. 2021

Cell Death Dis

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Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to cardiac fibrosis and heart failure (HF). Recent studies have demonstrated that EndMT is regulated by autophagy, and we previously showed suppression of excessive autophagy and alleviation of cardiac fibrosis in HF mice with inactivated receptor for advanced glycation end products (RAGE). Thus, we investigated whether reduced cardiac fibrosis due to RAGE knockout occurred by inhibiting EndMT mediated by excessive autophagy. We found a decrease in endothelial cells (CD31+/VE-Cadherin+) and an increase in cells co-expressing CD31 and α-smooth muscle actin (α-SMA, myofibroblast marker) at 8 weeks in heart tissue of mice subjected to transverse aortic constriction (TAC), which implied EndMT. Knockout RAGE decreased EndMT accompanied by decreased expression of autophagy-related proteins (LC3BII/I and Beclin 1), and alleviated cardiac fibrosis and improved cardiac function in TAC mice. Moreover, 3-methyladenine (3-MA) and chloroquine (CQ), inhibitors of autophagy, attenuated EndMT, and cardiac fibrosis in TAC mice. Importantly, EndMT induced by AGEs could be blocked by autophagy inhibitor in vivo and in vitro. These results suggested that AGEs/RAGE-autophagy-EndMT axis involved in the development of cardiac fibrosis and knockout RAGE ameliorated cardiac fibrosis through decreasing EndMT regulated by autophagy, which could be a promising therapeutic strategy for HF.

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Section: Methodsmentioning

confidence: 99%

Knockout RAGE alleviates cardiac fibrosis through repressing endothelial-to-mesenchymal transition (EndMT) mediated by autophagy

Zhang

Wang

et al. 2021

Cell Death Dis

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“…Tom20 is oxidized by iron-activated ROS signaling and triggers pyroptosis of melanoma cells by inducing GSDME cleavages [ 126 ]. Mixed-lineage kinase 3 (MLK3) regulated pyroptosis through NF-kB/NLRP3 signaling and ferroptosis via JNK/p53 pathway during myocardial fibrosis [ 127 ]. Transcription Factor p53 prompted pyroptosis to suppress tumor growth in NSCLC patients [ 128 , 129 ].…”

Section: Pyroptosis In Cancer Metastasismentioning

confidence: 99%

Non-coding RNAs in necroptosis, pyroptosis and ferroptosis in cancer metastasis

et al. 2021

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Distant metastasis is the main cause of death for cancer patients. Recently, the newly discovered programmed cell death includes necroptosis, pyroptosis, and ferroptosis, which possesses an important role in the process of tumor metastasis. At the same time, it is widely reported that non-coding RNA precisely regulates programmed death and tumor metastasis. In the present review, we summarize the function and role of necroptosis, pyrolysis, and ferroptosis involving in cancer metastasis, as well as the regulatory factors, including non-coding RNAs, of necroptosis, pyroptosis, and ferroptosis in the process of tumor metastasis.

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“…Intriguingly, beyond triggering inflammation, the NLRP3 inflammasome-dependent pyroptosis has also been brought to the forefront 33 . Previous studies have demonstrated that the NLRP3 inflammasome locates in diverse cardiac cells, such as cardiomyocytes, fibroblasts, endothelial cells and macrophages 28 , 34 – 37 . Importantly, the NLRP3 inflammasome may have cell-intrinsic roles in the different cell types.…”

Section: Discussionmentioning

confidence: 99%

Rosuvastatin protects against coronary microembolization-induced cardiac injury via inhibiting NLRP3 inflammasome activation

Chen

Zhou

et al. 2021

Cell Death Dis

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Coronary microembolization (CME), a common reason for periprocedural myocardial infarction (PMI), bears very important prognostic implications. However, the molecular mechanisms related to CME remain largely elusive. Statins have been shown to prevent PMI, but the underlying mechanism has not been identified. Here, we examine whether the NLRP3 inflammasome contributes to CME-induced cardiac injury and investigate the effects of statin therapy on CME. In vivo study, mice with CME were treated with 40 mg/kg/d rosuvastatin (RVS) orally or a selective NLRP3 inflammasome inhibitor MCC950 intraperitoneally (20 mg/kg/d). Mice treated with MCC950 and RVS showed improved cardiac contractile function and morphological changes, diminished fibrosis and microinfarct size, and reduced serum lactate dehydrogenase (LDH) level. Mechanistically, RVS decreased the expression of NLRP3, caspase-1, interleukin-1β, and Gasdermin D N-terminal domains. Proteomics analysis revealed that RVS restored the energy metabolism and oxidative phosphorylation in CME. Furthermore, reduced reactive oxygen species (ROS) level and alleviated mitochondrial damage were observed in RVS-treated mice. In vitro study, RVS inhibited the activation of NLRP3 inflammasome induced by tumor necrosis factor α plus hypoxia in H9c2 cells. Meanwhile, the pyroptosis was also suppressed by RVS, indicated by the increased cell viability, decreased LDH and propidium iodide uptake in H9c2 cells. RVS also reduced the level of mitochondrial ROS generation in vitro. Our results indicate the NLRP3 inflammasome-dependent cardiac pyroptosis plays an important role in CME-induced cardiac injury and its inhibitor exerts cardioprotective effect following CME. We also uncover the anti-pyroptosis role of RVS in CME, which is associated with regulating mitochondrial ROS.

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Pyroptosis and ferroptosis induced by mixed lineage kinase 3 (MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload

Cited by 150 publications

References 76 publications

Knockout RAGE alleviates cardiac fibrosis through repressing endothelial-to-mesenchymal transition (EndMT) mediated by autophagy

Knockout RAGE alleviates cardiac fibrosis through repressing endothelial-to-mesenchymal transition (EndMT) mediated by autophagy

Non-coding RNAs in necroptosis, pyroptosis and ferroptosis in cancer metastasis

Rosuvastatin protects against coronary microembolization-induced cardiac injury via inhibiting NLRP3 inflammasome activation

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