m6A methyltransferase WTAP regulates myocardial ischemia reperfusion injury through YTHDF1/FOXO3a signaling

Wang, Hui; Fu, Liujing; Li, Yin; Wei, Liudong; Gu, Xiufeng; Li, Huanming; Li, Jie; Wen, Shangyu

doi:10.1007/s10495-023-01818-4

Cited by 8 publications

(3 citation statements)

References 32 publications

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“…By binding to methylated RNA, WTAP recruits factors that can either stabilize or degrade the RNA molecule, thus regulating its half-life and overall abundance in the cell (12). Previous work has shown that WTAP enhances FOXO3a mRNA stability by triggering installation of m6A modification on its mRNA to promote H/R-induced apoptosis and inflammation in rat cardiomyocytes (23). WTAP increased ATF4 protein expression by regulating m6A modification of ATF4 mRNA to promote myocardial ischemia/reperfusion injury (24).…”

Section: Discussionmentioning

confidence: 99%

WTAP-mediated m6A modification of KLF6 aggravates hypoxia/reoxygenation-induced human cardiomyocyte injury

Fang,

Li,

2024

Shock

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Background Myocardial infarction (MI) is a severe condition that typically results from the ischemia and necrosis of heart muscle. Kruppel-like factor 6 (KLF6) can aggravate myocardial ischemia/reperfusion injury. This work aims to reveal its role and mechanism in hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury. Methods Human cardiomyocyte (AC16) was exposed to hypoxic treatment to mimic MI-like cell injury. mRNA expression levels of KLF6 and WT1 associated protein (WTAP) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was detected by western blotting assay. Cell viability was assessed by CCK-8 assay. Cell apoptosis and cell cycle were investigated by flow cytometry. Enzyme-linked immunosorbent assays were conducted to detect IL-1β, TNF-α and IL-6 levels. Fe2+ colorimetric assay kit was used to detect Fe2+ level. MDA Content Assay Kit was used to detect MDA level. Cellular ROS Assay kit was applied to assess ROS level. The association of KLF6 and WTAP was identified by RNA immunoprecipitation assay and dual-luciferase reporter assay. Results KLF6 and WTAP expression at mRNA and protein levels were significantly upregulated in serum samples of MI patients and H/R-induced AC16 cells when compared with control groups. KLF6 silencing attenuated H/R-induced AC16 cell apoptosis, inflammatory response, oxidative stress and ferroptosis. Additionally, WTAP stabilized KLF6 mRNA by regulating its m6A modification. Further, WTAP knockdown rescued H/R-induced AC16 cell apoptosis, inflammatory response, oxidative stress and ferroptosis by decreasing KLF6 expression. Conclusion WTAP-mediated m6A modification of KLF6 aggravated hypoxia/reoxygenation-induced apoptosis, inflammatory response, oxidative stress and ferroptosis of human cardiomyocytes, providing a therapeutic strategy for MI.

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Section: Discussionmentioning

confidence: 99%

WTAP-mediated m6A modification of KLF6 aggravates hypoxia/reoxygenation-induced human cardiomyocyte injury

Fang,

Li,

2024

Shock

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“…The potential regulatory efect of m6A modifcation may infuence the occurrence and development of a variety of cardiovascular diseases [ 22 ]. Studies have shown that Wilms tumor 1-associated protein (WTAP) is a RNA methyltransferase that promotes myocardial I/R injury progression and mediates lncRNA m6A modifcation through m 6 A reader [ 23 , 24 ]. Prediction analysis by SRAMP database revealed multiple m6A modifcation sites in lncRNA SNHG1 sequence.…”

Section: Introductionmentioning

confidence: 99%

WTAP-mediated m6A modification of lncRNA Snhg1 improves myocardial ischemia-reperfusion injury via miR-361-5p/OPA1-dependent mitochondrial fusion

Liu,

Wu,

et al. 2024

J Transl Med

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Background Myocardial ischemia-reperfusion injury (MIRI) is caused by reperfusion after ischemic heart disease. LncRNA Snhg1 regulates the progression of various diseases. N6-methyladenosine (m6A) is the frequent RNA modification and plays a critical role in MIRI. However, it is unclear whether lncRNA Snhg1 regulates MIRI progression and whether the lncRNA Snhg1 was modified by m6A methylation. Methods Mouse cardiomyocytes HL-1 cells were utilized to construct the hypoxia/reoxygenation (H/R) injury model. HL-1 cell viability was evaluated utilizing CCK-8 method. Cell apoptosis, mitochondrial reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were quantitated utilizing flow cytometry. RNA immunoprecipitation and dual-luciferase reporter assays were applied to measure the m6A methylation and the interactions between lncRNA Snhg1 and targeted miRNA or target miRNAs and its target gene. The I/R mouse model was constructed with adenovirus expressing lncRNA Snhg1. HE and TUNEL staining were used to evaluate myocardial tissue damage and apoptosis. Results LncRNA Snhg1 was down-regulated after H/R injury, and overexpressed lncRNA Snhg1 suppressed H/R-stimulated cell apoptosis, mitochondrial ROS level and polarization. Besides, lncRNA Snhg1 could target miR-361-5p, and miR-361-5p targeted OPA1. Overexpressed lncRNA Snhg1 suppressed H/R-stimulated cell apoptosis, mitochondrial ROS level and polarization though the miR-361-5p/OPA1 axis. Furthermore, WTAP induced lncRNA Snhg1 m6A modification in H/R-stimulated HL-1 cells. Moreover, enforced lncRNA Snhg1 repressed I/R-stimulated myocardial tissue damage and apoptosis and regulated the miR-361-5p and OPA1 levels. Conclusion WTAP-mediated m6A modification of lncRNA Snhg1 regulated MIRI progression through modulating myocardial apoptosis, mitochondrial ROS production, and mitochondrial polarization via miR-361-5p/OPA1 axis, providing the evidence for lncRNA as the prospective target for alleviating MIRI progression.

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“…7 Ferroptosis is an iron-dependent subtype of programmed cell death (iron-dependent type) involved in oxidative stress-induced cell death. [8][9][10] Several studies have demonstrated that redox imbalance plays an important role in OA development. Previous studies have indicated that iron can trigger bovine articular cartilage degeneration by enhancing the release of sulfated glycosaminoglycan.…”

Section: Introductionmentioning

confidence: 99%

IGF2BP1 Bolsters the Chondrocytes Ferroptosis of Osteoarthritis by Targeting m6A/MMP3 Axis

Zhao,

Dong,

Yang

et al. 2024

IJGM

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Chondrocyte degeneration and senescence are characteristics of osteoarthritis (OA) and other joint degenerative diseases, and ferroptosis has been observed to regulate the development of OA. However, the role of the N 6 -methyladenosine (m 6 A) modification in OA ferroptosis remains unclear. Methods: This study performed series of assays to investigate the function of the m 6 A reader IGF2BP1 in OA ferroptosis, including m 6 A quantitative analysis, Iron (Fe 2+ ) release analysis, Malondialdehyde (MDA) measurement, lipid peroxidation (ROS) detection and Glutathione (GSH) measurement. The molecular interaction and mechanism analysis was performed by Luciferase reporter assay, mRNA stability analysis and RNA immunoprecipitation (RIP) assay. Results: These results indicate that IGF2BP1 is upregulated in IL-1β-induced chondrocytes. Functionally, IGF2BP1 silencing represses ferroptosis, including iron (Fe 2+ ) accumulation, malondialdehyde, and reactive oxygen species (ROS). Mechanistically, among the potential downstream targets, matrix metalloproteinase-3 (MMP3) was observed to harbor a significant m 6 A modified site in the 3'-UTR. IGF2BP1 combines with MMP3 through the binding of m 6 A sites, thereby enhancing MMP3 mRNA stability. Discussion: In conclusion, our findings revealed the functions and mechanisms of m 6 A regulator IGF2BP1 in OA chondrocyte's ferroptosis, providing a novel target for OA treatment.

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m6A methyltransferase WTAP regulates myocardial ischemia reperfusion injury through YTHDF1/FOXO3a signaling

Cited by 8 publications

References 32 publications

WTAP-mediated m6A modification of KLF6 aggravates hypoxia/reoxygenation-induced human cardiomyocyte injury

WTAP-mediated m6A modification of KLF6 aggravates hypoxia/reoxygenation-induced human cardiomyocyte injury

WTAP-mediated m6A modification of lncRNA Snhg1 improves myocardial ischemia-reperfusion injury via miR-361-5p/OPA1-dependent mitochondrial fusion

IGF2BP1 Bolsters the Chondrocytes Ferroptosis of Osteoarthritis by Targeting m6A/MMP3 Axis

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