品牌：Virogen
货号：101-A
代理：靶点科技
名称：ANTI-GLUTATHIONE MAB 100
论文题目：Modifications of Sarcoplasmic Reticulum Function Prevent Progression of Sarcomere-Linked Hypertrophic Cardiomyopathy Despite a Persistent Increase in Myofilament Calcium Response
期刊：Front Physiol. 2020
摘要：肥厚型心肌病（HCM）是一种遗传性疾病，由主要编码肌丝蛋白的不同基因突变引起，因此被称为“肌节病”。尽管在近 30 年前发现了与 HCM 相关的肌节蛋白突变，但导致这种疾病发展的细胞机制尚不清楚，并且可能因不同突变而异。此外，尽管为开发HCM的有效治疗方法做出了许多努力，但这些方法基本上没有成功，需要更多的研究来更好地了解该疾病的细胞机制。在此报告的实验中，我们研究了表达突变体 cTn-R92Q 的小鼠模型，该突变体与 HCM 有关并诱导肌原丝 Ca2+ 敏感性和舒张功能障碍的增加。我们发现，磷酸蓝烷敲除 （PLNKO） 对舒张功能障碍的早期纠正能够阻止肌钙蛋白 T （Tn）-R92Q 转基因 （TG） 小鼠中 HCM 表型的发展。生成4组FVB/N背景小鼠并用于实验：（1）非转基因（NTG）/PLN小鼠，表达野生型Tn和正常PLN水平;（2）NTG/PLNKO小鼠，表达野生型Tn，无PLN;（3）TG/PLN小鼠，表达Tn-R92Q和PLN正常水平;（4） TG/PLNKO 小鼠，表达 Tn-R92Q 且无 PLN。 使用标准超声心动图参数和斑点跟踪应变测量值确定心脏功能。我们发现 TG/PLN 小鼠的心房形态和舒张功能均发生改变，但 TG/PLNKO 小鼠正常。组织学分析显示，仅在 TG/PLN 心脏中出现肌细胞紊乱和胶原沉积增加。我们还观察到仅在 TG/PLN 心脏中增加 Ca2+/钙调蛋白依赖性蛋白激酶 II （CaMKII） 磷酸化，但在 TG/PLNKO 心脏中没有。HCM 表型的挽救与 TG/PLN 和 TG/PLNKO 小鼠之间肌丝 Ca2+ 敏感性的差异无关。此外，与射血分数 （EF） 等标准收缩回声参数相比，散斑应变测量提供了一种更灵敏的方法来检测 TG/PLN 小鼠的早期收缩功能障碍。总之，我们的结果表明，通过改变 Ca2+ 通量而不改变肌丝对 Ca2+ 的反应来靶向舒张功能障碍能够阻止 HCM 表型的发展，应被视为 HCM 患者的潜在额外治疗方法。
Abstract: Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in different genes mainly encoding myofilament proteins and therefore called a “disease of the sarcomere.” Despite the discovery of sarcomere protein mutations linked to HCM almost 30 years ago, the cellular mechanisms responsible for the development of this disease are not completely understood and likely vary among different mutations. Moreover, despite many efforts to develop effective treatments for HCM, these have largely been unsuccessful, and more studies are needed to better understand the cellular mechanisms of the disease. In experiments reported here, we investigated a mouse model expressing the mutant cTn-R92Q, which is linked to HCM and induces an increase in myofilament Ca2+ sensitivity and diastolic dysfunction. We found that early correction of the diastolic dysfunction by phospholamban knockout (PLNKO) was able to prevent the development of the HCM phenotype in troponin T (Tn)-R92Q transgenic (TG) mice. Four groups of mice in FVB/N background were generated and used for the experiments: (1) non-transgenic (NTG)/PLN mice, which express wild-type Tn and normal level of PLN; (2) NTG/PLNKO mice, which express wild-type Tn and no PLN; (3) TG/PLN mice, which express Tn-R92Q and normal level of PLN; (4) TG/PLNKO mice, which express Tn-R92Q and no PLN. Cardiac function was determined using both standard echocardiographic parameters and speckle tracking strain measurements. We found that both atrial morphology and diastolic function were altered in TG/PLN mice but normal in TG/PLNKO mice. Histological analysis showed a disarray of myocytes and increased collagen deposition only in TG/PLN hearts. We also observed increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation only in TG/PLN hearts but not in TG/PLNKO hearts. The rescue of the HCM phenotype was not associated with differences in myofilament Ca2+ sensitivity between TG/PLN and TG/PLNKO mice. Moreover, compared to standard systolic echo parameters, such as ejection fraction (EF), speckle strain measurements provided a more sensitive approach to detect early systolic dysfunction in TG/PLN mice. In summary, our results indicate that targeting diastolic dysfunction through altering Ca2+ fluxes with no change in myofilament response to Ca2+ was able to prevent the development of the HCM phenotype and should be considered as a potential additional treatment for HCM patients.
谷胱甘肽检测抗体：
