Myocardial infarction(MI)is characterized by focal necrosis resulting from prolonged myocardial ischemia due to coronary artery obstruction.Vascular reconstruction following MI is crucial for improving cardiac functio...Myocardial infarction(MI)is characterized by focal necrosis resulting from prolonged myocardial ischemia due to coronary artery obstruction.Vascular reconstruction following MI is crucial for improving cardiac function and preventing recurrent infarction.This study investigates the interaction between macrophages and endothelial cells in angiogenesis mediated by nicotinamide mononucleotide(NMN)-induced secretion of macrophage-derived exosomes.We focus on the role of U2 small nuclear RNA auxiliary factor 1(U2af1)gene,a member of the splicing factor serine and arginine(SR)gene family,in the regulation of angiogenesis.Through cardiac ultrasound,Masson staining,2,3,5-triphenyltetrazolium chloride(TTC)staining,Microfil vascular perfusion,and platelet and endothelial cell adhesion molecule 1(CD31)immunofluorescence staining,extracellular vesicles from NMN-stimulated macrophages were shown to exert a protective effect in MI,with proteomic analysis identifying U2AF1 as a candidate protein involved in MI protection.Plasma U2AF1 levels were measured in 70 MI patients,revealing significantly lower levels in individuals with poor coronary collateral vessel(CCV;Rentrop scores 0–1)than in those with good CCV(Rentrop scores 2–3).In both myocardial and hindlimb ischemia mouse models,overexpression of endothelial cell-specific adenoviral overexpression U2AF1 promoted angiogenesis in the heart and hindlimbs and improved cardiac function after MI.Mechanistic studies demonstrated that U2AF1 regulates the alternative splicing(AS)of Yes1-associated transcriptional regulator(Yap1)gene,influencing post-MI angiogenesis and cardiac function recovery.Collectively,our clinical findings suggest that U2AF1 may serve as a therapeutic target for coronary collateral angiogenesis following MI.Given the low immunogenicity and high biosafety of exosomes,this study provides a foundational basis and translational potential for exosome-based therapies in MI treatment.展开更多
目的观察U2AF1基因突变的成人急性髓系白血病(AML)患者的临床特征及预后。方法对2016年1月至2019年12月就诊于郑州大学第一附属医院的690例AML患者的病历资料进行回顾性分析。按U2AF1突变与否将患者分为U2AF1未突变组(652例)和U2AF1突变...目的观察U2AF1基因突变的成人急性髓系白血病(AML)患者的临床特征及预后。方法对2016年1月至2019年12月就诊于郑州大学第一附属医院的690例AML患者的病历资料进行回顾性分析。按U2AF1突变与否将患者分为U2AF1未突变组(652例)和U2AF1突变组(38例)。比较两组临床特征及预后。结果690例AML患者中,U2AF1突变率为5.5%,常合并ASXL1、NRAS、SETBP1等基因突变。与U2AF1未突变组相比,U2AF1突变组外周血白细胞计数(WBC)、骨髓原始细胞比率低,预后中等及不良染色体核型多见,+8核型较多(P<0.05)。在625例可评估疗效的AML患者中,单因素分析发现,U2AF1突变组中位总生存期(OS)、中位无进展生存期(PFS)较U2AF1未突变组短,完全缓解(CR)率、2 a OS率较U2AF1未突变组低(P<0.05)。与未突变组相比,U2AF1 S34F突变组CR率较低,中位OS较短(P<0.05);两者中位PFS比较,差异无统计学意义(P>0.05)。U2AF1 S34Y突变组中位PFS较未突变组短(P<0.05);两者CR率、中位OS比较,差异无统计学意义(P>0.05)。多因素分析发现,U2AF1突变是影响<60岁AML患者OS、PFS的独立危险因素,1~2个疗程内达CR、接受造血干细胞移植、CEBPA双突变是影响<60岁AML患者OS及PFS的有利因素(P<0.05)。结论U2AF1突变在AML患者中发生率低,常与其他基因突变共存,预后中等及不良染色体核型多见。不同突变位点的预后意义不同。U2AF1突变是年轻(<60岁)AML患者的预后不良因素。展开更多
基金supported by the National Natural Science Founda-tion of China(82370417,82330011,and U21A20339)the Science Fund for Distinguished Young Scholars of Heilongjiang Province(JQ2024H001)the Heilongjiang Provincial Postdoctoral Science Foundation(LBH-Z23212).
文摘Myocardial infarction(MI)is characterized by focal necrosis resulting from prolonged myocardial ischemia due to coronary artery obstruction.Vascular reconstruction following MI is crucial for improving cardiac function and preventing recurrent infarction.This study investigates the interaction between macrophages and endothelial cells in angiogenesis mediated by nicotinamide mononucleotide(NMN)-induced secretion of macrophage-derived exosomes.We focus on the role of U2 small nuclear RNA auxiliary factor 1(U2af1)gene,a member of the splicing factor serine and arginine(SR)gene family,in the regulation of angiogenesis.Through cardiac ultrasound,Masson staining,2,3,5-triphenyltetrazolium chloride(TTC)staining,Microfil vascular perfusion,and platelet and endothelial cell adhesion molecule 1(CD31)immunofluorescence staining,extracellular vesicles from NMN-stimulated macrophages were shown to exert a protective effect in MI,with proteomic analysis identifying U2AF1 as a candidate protein involved in MI protection.Plasma U2AF1 levels were measured in 70 MI patients,revealing significantly lower levels in individuals with poor coronary collateral vessel(CCV;Rentrop scores 0–1)than in those with good CCV(Rentrop scores 2–3).In both myocardial and hindlimb ischemia mouse models,overexpression of endothelial cell-specific adenoviral overexpression U2AF1 promoted angiogenesis in the heart and hindlimbs and improved cardiac function after MI.Mechanistic studies demonstrated that U2AF1 regulates the alternative splicing(AS)of Yes1-associated transcriptional regulator(Yap1)gene,influencing post-MI angiogenesis and cardiac function recovery.Collectively,our clinical findings suggest that U2AF1 may serve as a therapeutic target for coronary collateral angiogenesis following MI.Given the low immunogenicity and high biosafety of exosomes,this study provides a foundational basis and translational potential for exosome-based therapies in MI treatment.
文摘目的观察U2AF1基因突变的成人急性髓系白血病(AML)患者的临床特征及预后。方法对2016年1月至2019年12月就诊于郑州大学第一附属医院的690例AML患者的病历资料进行回顾性分析。按U2AF1突变与否将患者分为U2AF1未突变组(652例)和U2AF1突变组(38例)。比较两组临床特征及预后。结果690例AML患者中,U2AF1突变率为5.5%,常合并ASXL1、NRAS、SETBP1等基因突变。与U2AF1未突变组相比,U2AF1突变组外周血白细胞计数(WBC)、骨髓原始细胞比率低,预后中等及不良染色体核型多见,+8核型较多(P<0.05)。在625例可评估疗效的AML患者中,单因素分析发现,U2AF1突变组中位总生存期(OS)、中位无进展生存期(PFS)较U2AF1未突变组短,完全缓解(CR)率、2 a OS率较U2AF1未突变组低(P<0.05)。与未突变组相比,U2AF1 S34F突变组CR率较低,中位OS较短(P<0.05);两者中位PFS比较,差异无统计学意义(P>0.05)。U2AF1 S34Y突变组中位PFS较未突变组短(P<0.05);两者CR率、中位OS比较,差异无统计学意义(P>0.05)。多因素分析发现,U2AF1突变是影响<60岁AML患者OS、PFS的独立危险因素,1~2个疗程内达CR、接受造血干细胞移植、CEBPA双突变是影响<60岁AML患者OS及PFS的有利因素(P<0.05)。结论U2AF1突变在AML患者中发生率低,常与其他基因突变共存,预后中等及不良染色体核型多见。不同突变位点的预后意义不同。U2AF1突变是年轻(<60岁)AML患者的预后不良因素。
