环状RNA CHACR调控压力超负荷诱导心肌肥大和氧化应激损伤  

Circular RNA CHACR regulates pressure overload-induced cardiac hypertrophy and oxidative stress damage

作　　者：王霜 韩瑜 袁敏 曹济民 孙腾 Wang Shuang;Han Yu;Yuan Min;Cao Jimin;Sun Teng(Key Laboratory of Cellular Physiology at Shanxi Medical University,Ministry of Education,Key Laboratory of Cellular Physiology of Shanxi Province,and Department of Physiology,School of Basic Medicine,Shanxi Medical University,Taiyuan 030001,Shanxi Province,China)

机构地区：[1]山西医科大学细胞生理学教育部重点实验室,山西省细胞生理学重点实验室,山西医科大学基础医学院生理学系,山西省太原市030001

出　　处：《中国组织工程研究》2025年第25期5362-5373,共12页Chinese Journal of Tissue Engineering Research

基　　金：国家自然科学基金面上项目(82170294),项目负责人:孙腾;国家自然科学基金青年科学基金项目(81800268),项目负责人:孙腾;国家自然科学基金面上项目(82170523),项目负责人:曹济民;中央引导地方科技发展资金项目(YDZJSX2022A061),项目负责人:孙腾。

摘　　要：背景:病理性心肌肥大是多种心脏疾病的危险促进因素,但其发病机制仍未阐明。环状RNA与心肌肥大密切相关,然而环状RNA CHACR在心肌肥大中的作用及调控机制尚未见报道。目的:探究环状RNA CHACR在压力超负荷诱导心肌肥大中的作用及机制。方法:①心脏原位注射环状RNA CHACR过表达慢病毒1周后进行横向主动脉缩窄手术诱导小鼠心肌肥大。术后8周,计算心脏质量/胫骨长比值和肺质量/胫骨长比值,测量心肌细胞表面积,检测肥大标志基因表达水平和心肌纤维化程度,评估心功能。②H9c2心肌细胞给予环状RNA CHACR过表达慢病毒处理72 h,然后加入1μmol/L血管紧张素Ⅱ处理24 h诱导心肌细胞肥大。通过检测心肌细胞表面积、肥大标志基因表达水平、蛋白质/DNA比值评估细胞肥大情况,通过检测活性氧水平和线粒体膜电位评估氧化应激损伤情况。结果与结论:①在体内和体外心肌肥大模型中,环状RNA CHACR的表达水平均显著降低(P<0.01);②过表达环状RNA CHACR显著抑制了横向主动脉缩窄手术诱导的小鼠心肌肥大表型,主要表现为心脏体积减小、心脏质量/胫骨长比值显著降低(P<0.05),肺质量/胫骨长比值显著降低(P<0.05),心肌细胞表面积显著减小(P<0.05),以及心肌肥大相关标志基因心房利钠肽(P<0.05)、脑钠肽(P<0.05)表达水平降低;③过表达环状RNA CHACR显著抑制了横向主动脉缩窄手术诱导的小鼠心脏纤维化,表现为纤维化面积减小(P<0.01)和纤维化标志基因Acta1的表达水平降低(P<0.05);④过表达环状RNA CHACR显著改善了小鼠心功能,主要表现为射血分数(P<0.05)和短轴缩短率(P<0.01)显著升高;(5)过表达环状RNA CHACR显著抑制了血管紧张素Ⅱ诱导的心肌细胞肥大,主要表现为心肌细胞表面积显著减小(P<0.05),心房利钠肽(P<0.05)和脑钠肽(P<0.05)表达水平显著下调,以及蛋白质/DNA比值显著减小(P<0.05);(6)过表达环�BACKGROUND:Pathological cardiac hypertrophy is a risk factor for various heart diseases,but its pathogenesis remains unclear.Circular RNAs are strongly associated with cardiac hypertrophy.However,the role of circular RNA CHACR in cardiac hypertrophy and its regulatory mechanisms have not been clarified.OBJECTIVE:To investigate the role of circular RNA CHACR in pressure overload-induced cardiac hypertrophy and the underlying mechanisms.METHODS:(1)Transverse aortic constriction was used to induce cardiac hypertrophy in vivo after in situ injection of cyclic RNA CHACR overexpressing lentivirus into the heart for 1 week.Heart mass/tibia length ratio and lung mass/tibia length ratio were calculated;cardiomyocyte surface area was measured;hypertrophic marker gene expression levels were detected;myocardial fibrosis degree was detected,and cardiac function was assessed.(2)H9c2 cardiomyocytes were treated with circular RNA CHACR overexpressing lentivirus for 72 hours,and then treated with 1μmol/L angiotensin II for 24 hours to induce hypertrophy of cardiomyocytes.The hypertrophy was assessed by measuring the surface area of cardiomyocytes,the expression level of hypertrophic marker genes,and the protein/DNA ratio.Oxidative stress damage was assessed by detecting reactive oxygen species levels and mitochondrial membrane potential.RESULTS AND CONCLUSION:(1)The expression level of circular RNA CHACR was significantly decreased in both in vivo and in vitro myocardial hypertrophy models(P<0.01).(2)The overexpression of circular RNA CHACR significantly inhibited the cardiac hypertrophy induced by transverse aortic constriction,including reducing the enlarged heart volume,significantly decreasing the increased heart mass/tibia length ratio(P<0.05),lung mass/tibia length ratio(P<0.05),and cardiomyocyte surface area(P<0.05),and decreasing the upregulated expression levels of hypertrophic markers atrial natriuretic peptide(P<0.05)and brain natriuretic peptide(P<0.05).(3)Cardiac fibrosis induced by transverse aortic constriction in

关 键 词：心肌肥大 环状RNA CHACR 血管紧张素Ⅱ 横向主动脉缩窄手术 氧化应激损伤 

分 类 号：R459.9[医药卫生—治疗学] R318[医药卫生—临床医学] R542.2