Kcnq1基因敲除对大鼠左心室和甲状腺功能的影响  

Effects of Kcnq1 gene knock-out on left ventricular and thyroid function in rats

作　　者：胡桑宇 王康 李丽[1,2,3] 彭鲁英[1,2,3] HU Sangyu;WANG Kang;LI Li;PENG Luying(School of Medicine,Tongji University,Shanghai 200331,China;State Key Laboratory of Cardiology,Shanghai East Hospital,School of Medicine,Tongji University,Shanghai 200120,China;Institute of Medical Genetics,Tongji University,Shanghai 200331,China)

机构地区：[1]同济大学医学院,上海200331 [2]同济大学心脏病全国重点实验室,上海200120 [3]同济大学医学遗传研究所,上海200331

出　　处：《同济大学学报（医学版）》2023年第4期476-484,共9页Journal of Tongji University(Medical Science)

基　　金：国家自然科学基金面上项目(32071109);上海市“科技创新行动计划”自然科学基金项目(21ZR1467000)。

摘　　要：目的探讨敲除钾电压门控通道亚家族Q成员1(potassium voltage-gated channel subfamily Q member 1,Kcnq1)对大鼠左心室结构和功能及甲状腺功能的影响。方法利用CRISPR/Cas9技术对大鼠的Kcnq1基因进行定点插入突变,构建Kcnq1纯合敲除大鼠模型。利用小动物超声成像系统检测大鼠的左心室结构和功能的变化。采用PowerLab测定大鼠心电图。通过ELISA检测Kcnq1敲除后大鼠血清中促甲状腺激素(thyrotropin,TSH)、游离三碘甲腺原氨酸(free triiodothyronine,FT 3)和游离甲状腺素(free thyroxine,FT 4)的含量变化。通过腹腔注射左旋甲状腺素(levothyroxine,L-T 4),观察L-T 4替代治疗对Kcnq1^(-/-)大鼠的治疗作用。结果超声成像检测结果表明,9月龄Kcnq1^(-/-)大鼠收缩末期室间隔厚度和左心室后壁厚度均显著减小(P<0.05);左心室收缩末期内径和左心室收缩末期容积显著增大(P<0.05);左心室射血分数和缩短分数显著下降(P<0.01)。心电图结果显示,Kcnq1^(-/-)大鼠QT间期延长,并伴有心率减慢。ELISA结果表明,Kcnq1^(-/-)大鼠血清中FT 4和FT 3含量均明显降低(P<0.05),TSH的水平未明显变化。Kcnq1^(-/-)大鼠腹腔注射L-T 4替代治疗2周后,与野生型相比,左心室后壁厚度显著增加(P<0.05);左心室收缩末期内径显著降低(P<0.05);左心室射血分数和缩短分数有所增加;同时,Kcnq1^(-/-)大鼠的QT间期缩短,血清中FT 3和FT 4的水平增加。结论Kcnq1基因的敲除引起大鼠左心室功能的减弱和QT间期延长,并且其甲状腺功能减退;进行L-T 4替代治疗后,能一定程度改善大鼠左心室的功能。Objective To investigate the effects of potassium voltage-gated channel subfamily Q member 1(Kcnq1)on left ventricular function and thyroid function in rats.Methods The Kcnq1^(-/-)rats were constructed with site-directed insertional mutagenesis performed by CRISPR/Cas9 technique.The left ventricular structure and function of rats were detected by the ultrasound imaging system.The electrocardiogram of Kcnq1^(-/-)rats was tested via PowerLab system.The levels of thyrotropin(TSH),free triiodothyronine(FT 3)and free thyroxine(FT 4)in serum were measured by ELISA.The therapeutic effect of levothyroxine(L-T 4)on Kcnq1^(-/-)rats was explored by intraperitoneal injection of L-T 4.Results The ultrasound results showed the interventricular septal thickness at end-systole(IVSs)and left ventricular posterior wall thickness at end-systole(LVPWs)were significantly reduced(P<0.05),the left ventricular internal dimension at end-systole(LVIDs)and the left ventricular end-systolic volume(LVESV)were increased(P<0.05),and the ejection fraction(EF)and the fractional shortening(FS)were decreased(P<0.01)in 9-month-old Kcnq1^(-/-)rats.The electrocardiogram showed that the QT interval was prolonged and the heart rate was slowed.The ELISA results indicated that the levels of FT 4 and FT 3 were decreased in Kcnq1^(-/-)rats,and serum TSH level did not significantly change.Two weeks after intraperitoneal injection of L-T 4,the LVPWs of Kcnq1^(-/-)rats was significantly increased(P<0.05),and LVIDs was significantly decreased(P<0.05),and there was some increase in left ventricular EF and FS.In addition,L-T 4 treatment also shortened the QT interval and increased serum levels of FT 3 and FT 4 in Kcnq1^(-/-)rats.Conclusion Knockout of Kcnq1 gene can cause left ventricular dysfunction and prolongation of QT interval in rats,which may be related to the Kcnq1 deficiency-mediated thyroid dysfunction.

关 键 词：KCNQ1基因 左心室 甲状腺 QT间期 大鼠 

分 类 号：R541[医药卫生—心血管疾病]