Our data suggest that the impaired production of IL-12p40 and IL-27p28 behaves as risk factors for esophageal cancer occurrence. IL-12B gene rs3212227 CC/AC and IL-12Rβ1 gene 378 GG/GC genotypes, which associated with decreased IL-12p40 level, may contribute to esophageal cancer susceptibility.
Background and Purpose Ferroptosis is a new form of cell death
discovered in recent years. PH is a pulmonary circulatory disease
partially characterized by small pulmonary vessel remodeling and
fibrosis. However, researchers have not clearly determined whether
ferroptosis is involved in PH. Here, this study examined the role and
regulatory mechanism of ferroptosis in PH and pulmonary fibrosis.
Experimental Approach To evaluate the occurrence of ferroptosis in rat
PH models and in hypoxic PASMCs, MDA, GSH and iron assay were performed.
The therapeutic potential of ferroptosis inhibitor fer-1 was evaluated
using echocardiography, hemodynamic analysis and ventricular weight
measurement in rat PH models. Ferroptosis-related molecule was
determined by western blotting and RT-PCR. Changes in autophagy and
fibrosis were analyzed by western blotting analysis, RT-PCR and
immunofluorescence. Key Results Ferroptosis was existence in vivo and
vitro PH models. The fer-1 significantly improved the pathological
symptoms of PH and inhibited the occurrence of pulmonary vascular
fibrosis. GPX4 was significantly lower expression in PH models, and
serves as a key driver of PH-related ferroptosis. A KEGG pathway
analysis and RT-PCR detection revealed that GPX4 drives ferroptosis in
an autophagy-dependent manner. The RIP experiment verified that WTAP
bound to the GPX4 pre-mRNA, induced m6A methylation and promoted its
pre-mRNA degradation, thereby reducing the expression of GPX4 in hypoxic
PASMCs. Conclusion and Implications This study proposed ferroptosis as a
novel form of cell death in PH, and revealed the regulatory mechanism of
the ferroptosis in PH, which is based on GPX4 m6A methylation regulated
by WTAP.
Background
Aberrant expression of circular RNAs (circRNAs) contributes to the initiation and progression of pulmonary hypertension (PH). Hypoxia‐inducible factor (HIF) is a well‐known modulator of hypoxia‐induced PH. The role and underlying mechanism of circRNAs in the regulation of HIF expression remains elusive.
Methods and Results
We profiled pulmonary artery transcriptomes using RNA sequencing and screened circRNAs associated with hypoxia treatment. The expression of a novel circRNA, circ_chr11_67292179–67294612 (circ‐myh8), was increased by hypoxia in a time‐dependent manner. We evaluated the effects of circ‐myh8 overexpression by adeno‐associated virus or inhibition by short hairpin RNA on proliferation and cell cycling in mice and pulmonary artery smooth muscle cells. Overexpression of circ‐myh8 promotes PH under normoxia, and disruption of circ‐myh8 by short hairpin RNA mitigates PH in chronic hypoxic mice. Biologically, circ‐myh8 induces the proliferation and cell‐cycle progression of pulmonary artery smooth muscle cells in vivo and in vitro. Mechanistically, RNA pull‐down and RNA immunoprecipitation assays were used to examine the interaction of circRNAs with the binding protein KAT7 (lysine acetyltransferase 7). The acetylation level of lysine 5 of histone H4 in the transcriptional initiation region of HIF1α was determined by chromatin immunoprecipitation assay followed by reverse transcription‐quantitative polymerase chain reaction. Circ‐myh8 acts as a modular scaffold to recruit histone acetyltransferase KAT7 to the promoters of HIF1α, which elicits acetylation of lysine 5 of histone H4 in their promoters.
Conclusions
Our findings not only reveal the pivotal roles of circ‐myh8 in governing histone modification in anti‐PH treatment but also advocate triggering the circ‐myh8/KAT7/HIF1α pathway to combat PH.
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