品牌：Virogen

貨號：101-A

代理：靶點科技

名稱：ANTI-GLUTATHIONE MAB 100

論文題目：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）是一種遺傳性疾病，由主要編碼肌絲蛋白的不同基因突變引起，因此被稱為“肌節病"。盡管在近 30 年前發現了與 HCM 相關的肌節蛋白突變，但導致這種疾病發展的細胞機制尚不清楚，并且可能因不同突變而異。此外，盡管為開發HCM的有效治療方法做出了許多努力，但這些方法基本上沒有成功，需要更多的研究來更好地了解該疾病的細胞機制。在此報告的實驗中，我們研究了表達突變體 cTn-R92Q 的小鼠模型，該突變體與 HCM 有關并誘導肌原絲 Ca2+ 敏感性和舒張功能障礙的增加。我們發現，磷酸藍烷敲除 （PLNKO） 對舒張功能障礙的早期糾正能夠阻止肌鈣蛋白 T （Tn）-R92Q 轉基因 （TG） 小鼠中 HCM 表型的發展。生成4組FVB/N背景小鼠并用于實驗：（1）非轉基因（NTG）/PLN小鼠，表達野生型Tn和正常PLN水平;（2）NTG/PLNKO小鼠，表達野生型Tn，無PLN;（3）TG/PLN小鼠，表達Tn-R92Q和PLN正常水平;（4） TG/PLNKO 小鼠，表達 Tn-R92Q 且無 PLN。 使用標準超聲心動圖參數和斑點跟蹤應變測量值確定心臟功能。我們發現 TG/PLN 小鼠的心房形態和舒張功能均發生改變，但 TG/PLNKO 小鼠正常。組織學分析顯示，僅在 TG/PLN 心臟中出現肌細胞紊亂和膠原沉積增加。我們還觀察到僅在 TG/PLN 心臟中增加 Ca2+/鈣調蛋白依賴性蛋白激酶 II （CaMKII） 磷酸化，但在 TG/PLNKO 心臟中沒有。HCM 表型的挽救與 TG/PLN 和 TG/PLNKO 小鼠之間肌絲 Ca2+ 敏感性的差異無關。此外，與射血分數 （EF） 等標準收縮回聲參數相比，散斑應變測量提供了一種更靈敏的方法來檢測 TG/PLN 小鼠的早期收縮功能障礙?？傊覀兊慕Y果表明，通過改變 Ca2+ 通量而不改變肌絲對 Ca2+ 的反應來靶向舒張功能障礙能夠阻止 HCM 表型的發展，應被視為 HCM 患者的潛在額外治療方法。

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.

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