Cardiac fibrosis is one of the crucial pathological factors in the heart,and various cardiac conditions associated with excessive fibrosis can eventually lead to heart failure.However,the exact molecular mechanism of ...Cardiac fibrosis is one of the crucial pathological factors in the heart,and various cardiac conditions associated with excessive fibrosis can eventually lead to heart failure.However,the exact molecular mechanism of cardiac fibrosis remains unclear.In the present study,we show that a novel lnc RNA that we named cardiac fibrosis-associated regulator(CFAR)is a profibrotic factor in the heart.CFAR was upregulated in cardiac fibrosis and its knockdown attenuated the expression of fibrotic marker genes and the proliferation of cardiac fibroblasts,thereby ameliorating cardiac fibrosis.Moreover,CFAR acted as a ce RNA sponge for mi R-449a-5p and derepressed the expression of LOXL3,which we experimentally established as a target gene of mi R-449a-5p.In contrast to CFAR,mi R-449a-5p was found to be significantly downregulated in cardiac fibrosis,and artificial knockdown of mi R-449a-5p exacerbated fibrogenesis,whereas overexpression of mi R-449a-5p impeded fibrogenesis.Furthermore,we found that LOXL3 mimicked the fibrotic factor TGF-β1 to promote cardiac fibrosis by activating m TOR.Collectively,our study established CFAR as a new profibrotic factor acting through a novel mi R-449a-5p/LOXL3/m TOR axis in the heart and therefore might be considered as a potential molecular target for the treatment of cardiac fibrosis and associated heart diseases.展开更多
Objective This study aimed to investigate the potential mechanisms by which lysyl oxidase like 3(LOXL3)affects the autophagy in chondrocytes in osteoarthritis(OA),specifically through the activation of mammalian targe...Objective This study aimed to investigate the potential mechanisms by which lysyl oxidase like 3(LOXL3)affects the autophagy in chondrocytes in osteoarthritis(OA),specifically through the activation of mammalian target of rapamycin complex 1(mTORC1).Methods To establish an OA model,rats underwent anterior cruciate ligament transection(ACLT).Chondrocytes were isolated from cartilage tissues and cultured.Western blotting was performed to assess the expression of LOXL3,Rheb,phosphorylation of p70S6K(p-p70S6K,a downstream marker of mTORC1),and autophagy markers.The autophagy of chondrocytes was observed using an immunofluorescence assay.Results The expression levels of both LOXL3 and Rheb proteins were upregulated in chondrocytes isolated from the OA model cartilage,in comparison to those from the normal cartilage.The silencing of LOXL3 resulted in a decrease in the protein levels of Rheb and p-p70S6K,as well as an increase in the expression of autophagy-related proteins.Additionally,the effect of LOXL3 could be reversed through the silencing of Rheb.The results of the immunofluorescence assay confirmed the impact of LOXL3 and Rheb on chondrocyte autophagy.Conclusion LOXL3 inhibits chondrocyte autophagy by activating the Rheb and mTORC1 signaling pathways.展开更多
赖氨酰氧化酶样蛋白3 (lysyl oxidase like 3,LOXL3)属于LOX蛋白家族成员之一,是一种铜依赖性胺氧化酶,负责细胞外基质中胶原蛋白和弹性蛋白的交联。LOX蛋白家族还包括LOX、LOXL1、LOXL2和LOXL4。LOXL3基因存在两种转录本变体,分别为LOX...赖氨酰氧化酶样蛋白3 (lysyl oxidase like 3,LOXL3)属于LOX蛋白家族成员之一,是一种铜依赖性胺氧化酶,负责细胞外基质中胶原蛋白和弹性蛋白的交联。LOX蛋白家族还包括LOX、LOXL1、LOXL2和LOXL4。LOXL3基因存在两种转录本变体,分别为LOXL3-sv1和LOXL3-sv2,在人体正常组织中差异表达。LOXL3定位于胃癌细胞胞核,与胃癌的侵袭和预后不良相关。LOXL3蛋白在恶性肿瘤发生、发展中通过诱导上皮-间充质转化,促进肿瘤侵袭和转移;LOXL3与维持DNA稳定性和有丝分裂的蛋白质相互作用,促进肿瘤进展和持续增殖。该文现就LOXL3蛋白的结构、功能及其在人类恶性肿瘤发生、发展中的作用进行综述,以期为恶性肿瘤的临床诊断、治疗和筛选预后标志物,提供理论基础和参考依据。展开更多
基金supported by the National Natural Science Foundation of China(82070240,82073844,82070236,82270246)University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province(UNPYSCT-2020169)Harbin Medical University Marshal Initiative Funding(HMUMIF-21026)。
文摘Cardiac fibrosis is one of the crucial pathological factors in the heart,and various cardiac conditions associated with excessive fibrosis can eventually lead to heart failure.However,the exact molecular mechanism of cardiac fibrosis remains unclear.In the present study,we show that a novel lnc RNA that we named cardiac fibrosis-associated regulator(CFAR)is a profibrotic factor in the heart.CFAR was upregulated in cardiac fibrosis and its knockdown attenuated the expression of fibrotic marker genes and the proliferation of cardiac fibroblasts,thereby ameliorating cardiac fibrosis.Moreover,CFAR acted as a ce RNA sponge for mi R-449a-5p and derepressed the expression of LOXL3,which we experimentally established as a target gene of mi R-449a-5p.In contrast to CFAR,mi R-449a-5p was found to be significantly downregulated in cardiac fibrosis,and artificial knockdown of mi R-449a-5p exacerbated fibrogenesis,whereas overexpression of mi R-449a-5p impeded fibrogenesis.Furthermore,we found that LOXL3 mimicked the fibrotic factor TGF-β1 to promote cardiac fibrosis by activating m TOR.Collectively,our study established CFAR as a new profibrotic factor acting through a novel mi R-449a-5p/LOXL3/m TOR axis in the heart and therefore might be considered as a potential molecular target for the treatment of cardiac fibrosis and associated heart diseases.
基金the National Natural Science Foundation of China(No.81702187)Natural Science Foundation of Jiangxi Province(No.20202BAB206019)+4 种基金Science Fund for Distinguished Young Scholars of Jiangxi Province(No.20224ACB216018)Scientific Talents Grants of Jiangxi Province(No.S2018LQCQ0800)Scientific Grants of Health Commission of Jiangxi Province(No.20194048)Scientific Innovation Talents Grants of Ganzhou(No.2019-60-08)Leading Talents Grants and Ph.D.Programs Foundation of Ganzhou People’s Hospital(No.Bsqd2019003)and Academic leaders Program of Ganzhou Institutes of Health.
文摘Objective This study aimed to investigate the potential mechanisms by which lysyl oxidase like 3(LOXL3)affects the autophagy in chondrocytes in osteoarthritis(OA),specifically through the activation of mammalian target of rapamycin complex 1(mTORC1).Methods To establish an OA model,rats underwent anterior cruciate ligament transection(ACLT).Chondrocytes were isolated from cartilage tissues and cultured.Western blotting was performed to assess the expression of LOXL3,Rheb,phosphorylation of p70S6K(p-p70S6K,a downstream marker of mTORC1),and autophagy markers.The autophagy of chondrocytes was observed using an immunofluorescence assay.Results The expression levels of both LOXL3 and Rheb proteins were upregulated in chondrocytes isolated from the OA model cartilage,in comparison to those from the normal cartilage.The silencing of LOXL3 resulted in a decrease in the protein levels of Rheb and p-p70S6K,as well as an increase in the expression of autophagy-related proteins.Additionally,the effect of LOXL3 could be reversed through the silencing of Rheb.The results of the immunofluorescence assay confirmed the impact of LOXL3 and Rheb on chondrocyte autophagy.Conclusion LOXL3 inhibits chondrocyte autophagy by activating the Rheb and mTORC1 signaling pathways.
文摘赖氨酰氧化酶样蛋白3 (lysyl oxidase like 3,LOXL3)属于LOX蛋白家族成员之一,是一种铜依赖性胺氧化酶,负责细胞外基质中胶原蛋白和弹性蛋白的交联。LOX蛋白家族还包括LOX、LOXL1、LOXL2和LOXL4。LOXL3基因存在两种转录本变体,分别为LOXL3-sv1和LOXL3-sv2,在人体正常组织中差异表达。LOXL3定位于胃癌细胞胞核,与胃癌的侵袭和预后不良相关。LOXL3蛋白在恶性肿瘤发生、发展中通过诱导上皮-间充质转化,促进肿瘤侵袭和转移;LOXL3与维持DNA稳定性和有丝分裂的蛋白质相互作用,促进肿瘤进展和持续增殖。该文现就LOXL3蛋白的结构、功能及其在人类恶性肿瘤发生、发展中的作用进行综述,以期为恶性肿瘤的临床诊断、治疗和筛选预后标志物,提供理论基础和参考依据。
