简冬冬
阜外华中心血管病医院 冠心病二病区
BACKGROUND:Cardiac-resident or -enriched microRNAs (miRNAs) could be released into the bloodstream becoming circulating cardiac miRNAs, which are increasingly recognized as non-invasive and accessible biomarkers of multiple heart diseases. However, dilated cardiomyopathy (DCM)-associated circulating miRNAs (DACMs) and their roles in DCM pathogenesis remain largely unexplored.METHODS:Two human cohorts, consisting of healthy individuals and DCM patients, were enrolled for serum miRNA sequencing (10 vs. 10) and quantitative polymerase chain reaction validation (46 vs. 54), respectively. Rigorous screening strategy was enacted to define DACMs and their potentials for diagnosis. DCM mouse model, different sources of cardiomyocytes, adeno-associated virus 9 (AAV9), gene knockout, RNAscope miRNA in situ hybridization, mRFP-GFP-LC3B reporter, echocardiography and transmission electron microscopy were adopted for mechanistic explorations.RESULTS:Serum miRNA sequencing revealed a unique expression pattern for DCM circulating miRNAs. DACMs miR-26a-5p, miR-30c-5p, miR-126-5p and miR-126-3p were found to be depleted in DCM circulation as well as heart tissues. Their expressions in circulation and heart tissues were proven to be correlated significantly, and a combination of these miRNAs was suggested potential values for DCM diagnosis. FOXO3, a predicted common target, was experimentally demonstrated to be co-repressed within cardiomyocytes by these DACMs except miR-26a-5p. Delivery of a combination of miR-30c-5p, miR-126-5p and miR-126-3p into the murine myocardium via AAV9 carrying an expression cassette driven by cTnT promoter, or cardiac-specific knockout of FOXO3 (Myh6-CreERT2 , FOXO3 flox+/+ ) dramatically attenuated cardiac apoptosis and autophagy involved in DCM progression. Moreover, competitively disrupting the interplay between DACMs and FOXO3 mRNA by specifically introducing their interacting regions into murine myocardium crippled the cardioprotection of DACMs against DCM.CONCLUSIONS:Circulating cardiac miRNA-FOXO3 axis plays a pivotal role in safeguarding against myocardial apoptosis and excessive autophagy in DCM development, which may provide serological cues for DCM non-invasive diagnosis and shed light on DCM pathogenesis and therapeutic targets.
Clinical and translational medicine 2023
Cold-inducible RNA-binding protein (CIRBP) is documented to be required for maintaining cardiac function, however, its role in chemotherapy-induced cardiotoxicity remains obscured. Herein, we report that CIRBP decreases cardiomyocyte apoptosis and attenuates cardiotoxicity through disrupting OGF-OGFR signal. CIRBP deficiency is involved in diverse chemotherapeutic agents induced cardiomyocyte apoptosis. Delivery of exogenous CIRBP to the mouse myocardium significantly mitigated doxorubicin-induced cardiac apoptosis and dysfunction. Specifically, OGFR was identified as a downstream core effector responsible for chemotherapy-induced cardiomyocyte apoptosis. CIRBP was shown to interact with OGFR mRNA and to repress OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced cardiac apoptosis was demonstrated to largely involve OGFR repression by CIRBP. NTX as a potent antagonist of OGFR successfully rescued CIRBP ablation-rendered susceptibility to cardiac dyshomeostasis upon exposure to doxorubicin, whereas another antagonist ALV acting only on opioid receptors did not. Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction by dampening OGF/OGFR axis, shedding new light on the mechanisms of chemo-induced cardiotoxicity and providing insights into the development of an efficacious cardioprotective strategy for cancer patients.
International journal of biological sciences 2022
BACKGROUND:Esophageal squamous cell carcinoma (ESCC) is the major type of esophageal cancer in China. The role of the bacteria present in ESCC tissue in neoplastic progression has not been fully elucidated. This study aimed to uncover different bacterial communities in ESCC tissues and examine the correlation between the abundance of the esophageal flora and clinicopathologic characteristics of ESCC.RESULTS:Microorganisms in tumors and normal tissues showed obvious clustering characteristics. The abundance of Fusobacterium (P = 0.0052) was increased in tumor tissues. The high level of Fusobacterium nucleatum was significantly associated with pT stage (P = 0.039) and clinical stage (P = 0.0039). The WES data showed that COL22A1, TRBV10-1, CSMD3, SCN7A and PSG11 were present in only the F. nucleatum-positive ESCC samples. GO and protein domain enrichment results suggested that epidermal growth factor might be involved in the regulation of cell apoptosis in F. nucleatum-positive ESCC. Both a higher mutational burden and F. nucleatum-positive was observed in tumors with metastasis than in tumors without metastasis.CONCLUSION:F. nucleatum is closely related to the pT stage and clinical stage of ESCC. The abundance of F. nucleatum and tumor mutation burden may be used in combination as a potential method to predict metastasis in ESCC.
BMC microbiology 2021
Aims: The N6-methyladenosine (m6A) modification plays an important role in various biological processes, but its role in atherosclerosis remains unknown. The aim of this study was to investigate the role and mechanism of m6A modification in endothelial cell inflammation and its influence on atherosclerosis development. Methods: We constructed a stable TNF-α-induced endothelial cell inflammation model and assessed the changes in the expression of m6A modification-related proteins to identify the major factors involved in this process. The m6A-modified mRNAs were identified by methylated RNA immunoprecipitation (RIP) sequencing and forkhead box O1 (FOXO1) was selected as a potential target. Through cytological experiments, we verified whether methyltransferase-like 14 (METTL14) regulates FOXO1 expression by regulating m6A-dependent mRNA and protein interaction. The effect of METTL14 on atherosclerosis development in vivo was verified using METTL14 knockout mice. Results: These findings confirmed that METTL14 plays major roles in TNF-α-induced endothelial cell inflammation. During endothelial inflammation, m6A modification of FOXO1, an important transcription factor, was remarkably increased. Moreover, METTL14 knockdown significantly decreased TNF-α-induced FOXO1 expression. RIP assay confirmed that METTL14 directly binds to FOXO1 mRNA, increases its m6A modification, and enhances its translation through subsequent YTH N6-methyladenosine RNA binding protein 1 recognition. Furthermore, METTL14 was shown to interact with FOXO1 and act directly on the promoter regions of VCAM-1 and ICAM-1 to promote their transcription, thus mediating endothelial cell inflammatory response. In vivo experiments showed that METTL14 gene knockout significantly reduced the development of atherosclerotic plaques. Conclusion: METTL14 promotes FOXO1 expression by enhancing its m6A modification and inducing endothelial cell inflammatory response as well as atherosclerotic plaque formation. Decreased expression of METTL14 can inhibit endothelial inflammation and atherosclerosis development. Therefore, METTL14 may serve as a potential target for the clinical treatment of atherosclerosis.
Theranostics 2020
Nuclear receptor-binding SET domain 3 (NSD3) is a lysine methyltransferase that plays important roles in multiple biological activities; however; its potential roles in the cardiovascular system remain unknown. In this study, we found that NSD3 expression is reduced by isoproterenol (ISO) stimuli both in vitro and in vivo. Overexpression of NSD3 attenuates ISO-induced cardiomyocyte hypertrophy. Mechanistically, ISO treatment decreases H3K27me2/3 modifications on the atrial natriuretic factor (ANF) promoter by suppressing NSD3 and inhibits the association between NSD3 and bromodomain-containing protein 4 (BRD4), thus suppressing the BRD4-mediated H3K27ac modifications, which ultimately promote ANF transcription and cardiomyocyte hypertrophy. In conclusion, NSD3 decreases ANF expression and, thereby, attenuates ISO-induced cardiomyocyte hypertrophy.
FEBS letters 2019
