Ricolinostat驱动初级纤毛的解聚降低了X线损伤的心肌纤维化  

Ricolinostat reduces X-ray induced myocardial fibrosis and drives disassembly of primary cilia

作　　者：马承旭 马小妮 马丽华[1] 傅松波[1,3] 成建国[1,3] MA Cheng-xu;MA Xiao-ni;MA Li-hua;FU Song-bo;CHENG Jian-guo(Dept of Endocrinology,the First Hospital of Lanzhou University,Lanzhou 730000,China;Dept of Medical Laboratory Center,the First Hospital of Lanzhou University,Lanzhou 730000,China;Dept of Clinical Pharmacology,the First Clinical Medical College of Lanzhou University,Lanzhou 730000,China)

机构地区：[1]兰州大学第一医院内分泌科,甘肃兰州730000 [2]兰州大学第一医院医学检验中心,甘肃兰州730000 [3]兰州大学第一临床医学院内分泌专业临床药理基地,甘肃兰州730000

出　　处：《中国药理学通报》2024年第10期1844-1849,共6页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 82260050);甘肃省自然科学基金资助项目(No22JR5RA926);兰州市科技计划项目(No 2022-ZD-97)。

摘　　要：目的 评价Ricolinostat对X线辐射诱导心肌纤维化和心肌成纤维细胞初级纤毛损伤的影响。方法 8 Gy剂量单次全身照射Wistar大鼠,腹腔注射Ricolinostat, ELISA测定血清肌钙蛋白T(troponinT,TnT)和脑钠肽(brain natriuretic peptide, BNP)水平;HE和Masson染色检测心肌组织纤维化程度,免疫荧光检测心肌组织和心肌成纤维细胞初级纤毛及Ⅰ型胶原含量;qRT-PCR和Western blot检测心肌组织和心肌成纤维细胞组蛋白去乙酰化酶6(histone deacetylase 6,HDAC6)的基因和蛋白水平。结果 与对照组相比,X线辐射增加大鼠心肌组织胶原紊乱和Ⅰ型胶原含量,促进心肌成纤维细胞增殖,上调了心肌成纤维细胞中HDAC6的表达(P> 0.05),增加心肌组织和心肌成纤维细胞初级纤毛的形成。经过Ricolinostat治疗后,心肌组织和心肌成纤维细胞中HDAC6的表达水平和初级纤毛形成降低(P<0.05)。胶原纤维排列稍显整齐,胶原体积分数降低,血清中TnT(P<0.01)和BNP水平降低。结论 Ricolinostat能够驱动初级纤毛的解聚,降低了X线损伤诱导的心肌纤维化,具有治疗放射性心肌纤维化的潜在价值。Aim To evaluate the effect of ricolinostat on X-ray induced myocardial fibrosis and damage to primary cilia in myocardial fibroblasts.Methods Wistar rats were subjected to a single dose of 8 Gy whole-body irradiation,followed by intraperitoneal injection of ricolinostat.Serum troponinT(TnT)and brain natriuretic peptide(BNP)levels were measured using ELISA.The degree of myocardial tissue fibrosis was measured using HE and Masson staining.TypeⅠcollagen and primary cilia were detected using immunofluorescence.The gene and protein levels of histone deacetylase 6(HDAC6)in myocardial tissue and cells were detected using PCR and Western blot.Results Compared with the control group,X-ray radiation increased typeⅠcollagen content and promoted the proliferation of myocardial fibroblasts in rat myocardial tissue.X-ray radiation slightly up-regulated the expression of HDAC6 in myocardial fibroblasts(P>0.05),and significantly increased the formation of primary cilia in myocardial tissue and myocardial fibroblasts.After treatment with ricolinostat,the expression of HDAC6 and primary cilia formation decreased in myocardial tissue and myocardial fibroblasts(P<0.05),and acetylation in the cytoplasm significantly increased.The arrangement of collagen fibers in myocardial tissue was slightly neat,collagen volume fraction was reduced,and the levels of TnT(P<0.01)and BNP decreased.Conclusions Ricolinostat can mitigate X-ray induced myocardial fibrosis via the disassembly of primary cilia,with potential value for treating radiation-induced myocardial fibrosis.

关 键 词：Ricolinostat 初级纤毛 X线 HDAC6 心肌成纤维细胞 心肌纤维化 

分 类 号：R-332[医药卫生] R322.11R542.23R818R916.4