TRPC channels blockade abolishes endotoxemic cardiac dysfunction by hampering intracellular inflammation and Ca2+ leakage

Tang, Na; Tian, Wen; Ma, Guangyuan; Xiao, Xiyuan; Zhou, Lei; Li, Zezhi; Liu, Xiao-Xiao; Li, Chongyao; Wu, Ke-Han; Liu, Wenjuan; Gao, Yuanyuan; Yang, Xin; Qi, Jianzhao; Li, Ding; Liu, Yang; Chen, Wensheng; Gao, Jin‐Ming; Li, Xiao-Qiang; Cao, Wei

doi:10.1038/s41467-022-35242-0

Cited by 12 publications

(6 citation statements)

References 110 publications

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“…This disruption promotes the production of ROS within the mitochondria, inducing oxidative stress [ 70 , 71 ]. Moreover, cytoplasmic Ca 2+ overload can directly promote inflammatory responses and involve in the synthesis and release of multiple inflammatory factors [ 72 ]. Based on these findings, we speculate that the regulation of glucose metabolism, oxidative stress, and inflammation in C. nasus during air exposure could potentially be attributed to the cytoplasmic Ca 2+ overload.…”

Section: Discussionmentioning

confidence: 99%

Integrated mRNA and miRNA analysis reveals the regulatory network of oxidative stress and inflammation in Coilia nasus brains during air exposure and salinity mitigation

Gao,

Mang,

Liu

et al. 2024

BMC Genomics

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Background Air exposure is an inevitable source of stress that leads to significant mortality in Coilia nasus. Our previous research demonstrated that adding 10‰ NaCl to aquatic water could enhance survival rates, albeit the molecular mechanisms involved in air exposure and salinity mitigation remained unclear. Conversely, salinity mitigation resulted in decreased plasma glucose levels and improved antioxidative activity. To shed light on this phenomenon, we characterized the transcriptomic changes in the C. nasus brain upon air exposure and salinity mitigation by integrated miRNA-mRNA analysis. Results The plasma glucose level was elevated during air exposure, whereas it decreased during salinity mitigation. Antioxidant activity was suppressed during air exposure, but was enhanced during salinity mitigation. A total of 629 differentially expressed miRNAs (DEMs) and 791 differentially expressed genes (DEGs) were detected during air exposure, while 429 DEMs and 1016 DEGs were identified during salinity mitigation. GO analysis revealed that the target genes of DEMs and DEGs were enriched in biological process and cellular component during air exposure and salinity mitigation. KEGG analysis revealed that the target genes of DEMs and DEGs were enriched in metabolism. Integrated analysis showed that 24 and 36 predicted miRNA-mRNA regulatory pairs participating in regulating glucose metabolism, Ca2+ transport, inflammation, and oxidative stress. Interestingly, most of these miRNAs were novel miRNAs. Conclusion In this study, substantial miRNA-mRNA regulation pairs were predicted via integrated analysis of small RNA sequencing and RNA-Seq. Based on predicted miRNA-mRNA regulation and potential function of DEGs, miRNA-mRNA regulatory network involved in glucose metabolism and Ca2+ transport, inflammation, and oxidative stress in C. nasus brain during air exposure and salinity mitigation. They regulated the increased/decreased plasma glucose and inhibited/promoted antioxidant activity during air exposure and salinity mitigation. Our findings would propose novel insights to the mechanisms underlying fish responses to air exposure and salinity mitigation.

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Section: Discussionmentioning

confidence: 99%

Integrated mRNA and miRNA analysis reveals the regulatory network of oxidative stress and inflammation in Coilia nasus brains during air exposure and salinity mitigation

Gao,

Mang,

Liu

et al. 2024

BMC Genomics

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“…Consistently, suppression of IP3R signaling can protect cardiac microvascular endothelial cells from oxidative stress injury (55). In addition, blocking IP3R is shown to compromise Ca 2+ leakage and inflammation burst in endotoxemic cardiac dysfunction (56). IP3R is known to regulate Ca 2+ overload to affect myocardial injury (57).…”

Section: Discussionmentioning

confidence: 99%

Cebpd Regulates Oxidative Stress and Inflammatory Responses in Hypertensive Cardiac Remodeling

Zhao,

Hu,

Zhang

et al. 2023

Shock

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Hypertension seems to inevitably cause cardiac remodeling, increasing the mortality of patients. This study aimed to explore the molecular mechanism of CCAAT enhancer binding protein delta (CEBPD)-mediated oxidative stress and inflammation in hypertensive cardiac remodeling. The hypertensive murine model was established through angiotensin-II (Ang II) injection and hypertensive mice underwent overexpressed CEBPD vector injection, cardiac function evaluation and observation of histological changes. The cell model was established by Ang II treatment and transfected with overexpressed CEBPD vector. Cell viability and surface area, oxidative stress [reactive oxygen species (ROS)/superoxide dismutase (SOD)/ superoxide dismutase (LDH)/MDA) were assessed and inflammatory factors (TNF-α/IL-1β/IL-6/IL-10) were determined both in vivo and in vitro. The levels of CEBPD, miR-96-5p, inositol 1,4,5-trisphosphate receptor 1 (IP3R), natriuretic peptide B, and natriuretic peptide A, collagen I, and collagen III in tissues and cells were determined. The binding relationships of CEBPD/miR-96-5p/IP3R 3’UTR were validated. CEBPD was reduced in cardiac tissue of hypertensive mice and CEBPD upregulation improved cardiac function and attenuated fibrosis and hypertrophy, along with reductions of ROS/LDH/MDA/TNF-α/IL-1β/IL-6 and increases in SOD/IL-10. CEBPD enriched on the miR-96-5p promoter to promote miR-96-5p expression, while CEBPD and miR-96-5p negatively regulated IP3R. miR-96-5p silencing/IP3R overexpression reversed the alleviative role of CEBPD overexpression in hypertensive mice. In summary, CEBPD promoted miR-96-5p to negatively regulate IP3R expression to inhibit oxidative stress and inflammation, thereby alleviating hypertensive cardiac remodeling.

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“…Endotoxemia causes a spectrum of negative effects on vascular endothelial function, including inflammation, hyperpermeability, and decreased barrier function, conducive to dysregulated hemostasis, hemodynamic disturbances, multiorgan dysfunction, and eventually death [ 1 , 2 ]. Microvascular dysfunction caused by endotoxemia has been directly linked to a reduction in myocardial perfusion, which is recognized as a potential contributor to the progression of endotoxemic cardiomyopathy [ 3 , 4 ]. This progression is driven by secretion of proinflammatory and chemotactic substances, increased vascular permeability, thrombosis, and interruption of myocardial blood flow and oxygen supply, resulting in cardiomyocyte ischemia, myocardial edema, and ultimately heart failure [ 5 – 8 ].…”

Section: Introductionmentioning

confidence: 99%

DNA-PKcs Phosphorylates Cofilin2 to Induce Endothelial Dysfunction and Microcirculatory Disorder in Endotoxemic Cardiomyopathy

Du,

Zhu,

et al. 2024

Research

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The presence of endotoxemia is strongly linked to the development of endothelial dysfunction and disruption of myocardial microvascular reactivity. These factors play a crucial role in the progression of endotoxemic cardiomyopathy. Sepsis-related multiorgan damage involves the participation of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). However, whether DNA-PKcs contributes to endothelial dysfunction and myocardial microvascular dysfunction during endotoxemia remains unclear. Hence, we conducted experiments in mice subjected to lipopolysaccharide (LPS)-induced endotoxemic cardiomyopathy, as well as assays in primary mouse cardiac microvascular endothelial cells. Results showed that endothelial-cell-specific DNA-PKcs ablation markedly attenuated DNA damage, sustained microvessel perfusion, improved endothelial barrier function, inhibited capillary inflammation, restored endothelium-dependent vasodilation, and improved heart function under endotoxemic conditions. Furthermore, we show that upon LPS stress, DNA-PKcs recognizes a TQ motif in cofilin2 and consequently induces its phosphorylation at Thr 25 . Phosphorylated cofilin2 shows increased affinity for F-actin and promotes F-actin depolymerization, resulting into disruption of the endothelial barrier integrity, microvascular inflammation, and defective eNOS-dependent vasodilation. Accordingly, cofilin2-knockin mice expressing a phospho-defective (T25A) cofilin2 mutant protein showed improved endothelial integrity and myocardial microvascular function upon induction of endotoxemic cardiomyopathy. These findings highlight a novel mechanism whereby DNA-PKcs mediates cofilin2 Thr25 phosphorylation and subsequent F-actin depolymerization to contribute to endotoxemia-related cardiac microvascular dysfunction.

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TRPC channels blockade abolishes endotoxemic cardiac dysfunction by hampering intracellular inflammation and Ca2+ leakage

Cited by 12 publications

References 110 publications

Integrated mRNA and miRNA analysis reveals the regulatory network of oxidative stress and inflammation in Coilia nasus brains during air exposure and salinity mitigation

Integrated mRNA and miRNA analysis reveals the regulatory network of oxidative stress and inflammation in Coilia nasus brains during air exposure and salinity mitigation

Cebpd Regulates Oxidative Stress and Inflammatory Responses in Hypertensive Cardiac Remodeling

DNA-PKcs Phosphorylates Cofilin2 to Induce Endothelial Dysfunction and Microcirculatory Disorder in Endotoxemic Cardiomyopathy

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