INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Daoxi Qi,Fan Wang,Xiaokang Zhang,Boyu Li,Wenjie Zhou,Shuyang Sheng,Ruiyang Zhu,Liang Cao,Chang Zhao,Xinyu Deng,Tanglin Ouyang,Fang Zheng
Inflammatory activation and dysfunction of immune cells are essential events in coronary artery disease (CAD) pathogenesis. C-type lectin domain family 5 member A (CLEC5A) has recently been regarded as a potent modulator of inflammation, while its contribution to CAD remains undefined. This study aims to clarify the involvement of CLEC5A in atherosclerosis and explore its epigenetic regulatory mechanisms. Integrated methylome and transcriptome analyses identified CLEC5A as a DNA methylation-driven gene in CAD. Functional studies revealed that DNMT1 overexpression suppresses CLEC5A expression in THP-1 cells, with subsequent identification of the cg06744540 CpG site as the critical regulatory locus. Clinical correlation analyses demonstrated that elevated CLEC5A expression is inversely associated with hypomethylation at cg06744540 in CAD patients. Furthermore, CLEC5A overexpression significantly enhanced monocyte inflammation, migration, and adhesion, promoted macrophage polarization and lipid accumulation, and inhibited apoptosis. Mechanistic investigations revealed that CLEC5A exacerbates inflammation in monocyte/macrophage by activating the NF-κB signaling pathway. Conversely, CLEC5A knockdown resulted in opposite effects. Notably, treatment of cells with folic acid, a methylation-enhancing factor, significantly increased DNMT1 expression and declined CLEC5A expression. Consistently, folic acid reversed high-fat-induced CLEC5A expression and inflammation and suppressed the formation of atherosclerotic plaques in vivo. In conclusion, the epigenetic upregulation of CLEC5A through DNMT1-mediated cg06744540 demethylation contributed to monocyte/macrophage dysfunction, thus accelerating CAD progression.
研究领域:
心血管病学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
BMC Cardiovascular Disorders
·
2024
·Vol. 24
·期 1
·1-13
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IF 2
Wang Xin,Sun Limin
MI (myocardial infarction) often triggers severe heart failure and is one of the leading causes of death worldwide. Receptor expression-enhancing protein 5 (REEP5), a member of REEPs, acts as regulators of endoplasmic reticulum (ER) affecting cardiac functions. Based on GSE114695 profile data, REEP5 was decreased in the left ventricle of MI mice. However, its role and potential mechanism in MI remain to be investigated. In the present study, the mouse MI model was established by ligation of the left anterior descending artery. REEP5 expression was downregulated in the infarct penumbra area of MI mice. Next, its role during MI was explored by gain-of-function. Interestingly, REEP5 overexpression improved left ventricular function of mice with MI, accompanied with reduced infarct size. In cardiomyocytes, REEP5 overexpression inhibited ER stress, accompanied with repressive phosphorylation of PERK and IRE1α, and the decreased nuclear translocation of ATF6. Subsequently, REEP5 overexpression downregulated the levels of Chop and cleaved caspase-12, further alleviating ER stress-induced apoptosis, which was consistent with the in vivo results. Moreover, REEP5 was found to bind to C-type lectin member 5 A (CLEC5A), a protein that triggers cardiac dysfunction. CLEC5A, whose expression was elevated in hypoxia-induced cell models, led to cardiomyocyte apoptosis. Noteworthily, REEP5 overexpression markedly abolished the effects of CLEC5A on ER stress-induced apoptosis. Taken together, REEP5 mediated the function of CLEC5A to relieve MI via inhibiting ER stress-induced apoptosis in vivo and in vitro. REEP5 may be a promising target for treating MI.
研究领域:
心脏病学
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分子生物学
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细胞生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
eNeuro
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2024
·
IF 2.7
Yonghong Tan,Qiong Wang,Yubing Guo,Na Zhang,Yingyi Xu,Xue Bai,Jianhua Liu,Xiaobao Bi
Pyroptosis, an inflammatory Programmed cell death, has recently been found to play an important role in spinal cord injury (SCI). C-type lectin domain family 5 member A (CLEC5A), triggering receptor expressed on myeloid cells 1 (TREM1), and NLR-family CARD-containing protein 4 (NLRC4) have been reported to be associated with neuronal pyroptosis, but few studies have clarified their functions and regulatory mechanisms in SCI. In this study, CLEC5A, TREM1, and NLRC4 were highly expressed in lidocaine-induced SCI rat models, and their knockdown alleviated lidocaine-induced SCI. The elevation of proptosis related indicators LDH, ASC, GSDMD-N, IL-18, caspase-1, and IL-1β levels in SCI rats was attenuated after silencing of CLEC5A, TREM1, or NLRC4. Lidocaine-induced the decrease in cell viability and the elevation in cell death were partly reversed after CLEC5A, TREM1, or NLRC4 silencing. Lidocaine-mediated effects on the levels of LDH, ASC, GSDMD-N, IL-18, caspase-1, and IL-1β in lidocaine-induced PC-12 cells were weakened by downregulating CLEC5A, TREM1, or NLRC4. CLEC5A could interact with TREM1 to mediate NLRC4 expression, thus accelerating neuronal pyroptosis, ultimately leading to SCI exacerbation. In conclusions, CLEC5A interacted with TREM1 to increase NLRC4 expression, thus promoting neuronal pyroptosis in rat SCI models, providing new insights into the role of neuronal pyroptosis in SCI.Significance statement Pyroptosis has been reported to be involved in SCI. Higher levels of CLEC5A, TREM1, and NLRC4 associated with neuronal pyroptosis. However, the role and regulatory mechanism of CLEC5A, TREM1, and NLRC4 in SCI were not clear. Here, high expression of CLEC5A, TREM1, and NLRC4 was observed in lidocaine-induced SCI rat models. CLEC5A could interact with TREM1 to enhance the expression of NLRC4, thus accelerating neuronal pyroptosis in rat SCI models. These findings identify CLEC5A, TREM1, and NLRC4 as potential therapeutic targets for SCI.
研究领域:
神经科学
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细胞生物学
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炎症
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脊髓损伤
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产品关联
DOI
PubMed
高影响因子
Biochemistry and Cell Biology
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2021
·Vol. 99
·期 5
·
IF 3.626
Xin Wang,Yu Hu,Yaguang Wang,Dapeng Shen,Guizhou Tao
Increasing evidence has shown that the NOD-like receptor protein 3 (NLRP3) inflammasome and pyroptotic cell death play vital roles in the pathophysiology of myocardial infarction (MI), a common cardiovascular disease characterized by cardiac dysfunction. C-type lectin member 5A (CLEC5A) has been reported to be strongly associated with activation of the NLRP3 inflammasome and pyroptosis. In this study, an in vivo MI model was established by ligation of the left anterior descending coronary artery in male C57BL/6 mice, and CLEC5A knockdown was further achieved by intra-myocardial injection of adenovirus delivering shRNA-CLEC5A. CLEC5A was found to be highly expressed in the left ventricle of MI mice, while CLEC5A knockdown alleviated cardiac dysfunction in MI mice. In addition, MI-induced classical activation of macrophages was significantly inhibited after CLEC5A silencing. Additionally, CLEC5A knockdown dramatically inhibited MI-triggered activation of NLRP3 inflammasome, pyroptosis, and NF-κB signaling in the left ventricle of mice. In vitro experiments further validated that CLEC5A knockdown suppressed M1 polarization in LPS/IFNγ-stimulated RAW264.7 cells and inhibited the polarized RAW264.7-induced activation of NLRP3 inflammasome/pyroptosis signaling in co-cultured cardiomyocytes. In conclusion, CLEC5A knockdown protects against MI-induced cardiac dysfunction by regulating macrophage polarization, NLRP3 inflammasome, and cell pyroptosis.
研究领域:
心血管疾病
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分子生物学
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免疫学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
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