Doxycycline decreases amyloidogenic light chain-induced autophagy in isolated primary cardiac myocytes.
Doxycycline decreases amyloidogenic light chain-induced autophagy in isolated primary cardiac myocytes.
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DOI：
10.1016/j.ijcard.2020.07.016
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发表时间：
2020-12-15
影响因子：
3.5
通讯作者：
Sam, Flora
中科院分区：
文献类型：
--
作者：
Valero-Munoz, Maria;Wilson, Richard M.;Breton-Romero, Rosa;Croteau, Dominique;Seldin, David C.;Sam, Flora
免疫球蛋白轻链（AL）心脏淀粉样变性的特征是淀粉样纤维在心脏细胞外沉积，具有潜在的致命性。未经治疗，其临床表现为心力衰竭，急剧下降，中位生存期<6个月。AL心脏淀粉样变性与心脏细胞外基质稳态受损和基质金属蛋白酶（MMP）水平升高有关。这篇文章为多西环素（一种非选择性MMP抑制剂）在AL心脏淀粉样变性中的潜在作用提供了新的见解。与未处理的心肌细胞相比，用AL刺激的成年大鼠心室肌细胞（从心脏淀粉样变性患者获得）增加MMP-2和MMP-9活性（P <0.05）;自噬标记物微管相关蛋白1 LC-3亚型II（LC 3-II）的表达（P <0.01），以及自噬相关蛋白ATG-4 B（P <0.05）和ATG-5（P <0.05）。强力霉素可抑制MMP活性（P <0.0001），并通过ATG-5降低AL诱导的自噬（P <0.05）。这些体外研究表明，多西环素，除了抑制MMP，还调制AL诱导的心肌细胞自噬，并提供了潜在的见解，为未来的治疗目标AL诱导的蛋白毒性。AL心脏淀粉样变性的心脏毒性和心力衰竭的新疗法仍然是一个重要的未满足的需求。
Immunoglobulin light chain (AL) cardiac amyloidosis is characterized by extracellular deposition of amyloid fibrils in the heart and is potentially fatal. Untreated, it manifests clinically as heart failure with a precipitous decline and a median survival of <6 months. AL cardiac amyloidosis is associated with impaired extracellular matrix homeostasis in the heart with increased matrix metalloproteinase (MMP) levels. This commmunication provides novel insights into a potential role for doxycycline, a non-selective MMP inhibitor in AL cardiac amyloidosis. Adult rat ventricular myocytes stimulated with AL (obtained from cardiac amyloidosis patients) increased MMP-2 and MMP-9 activities (P < .05); the expression of autophagy marker microtubule associated protein 1 LC-3 isoform II (LC3-II) (P < .01), and the autophagy-related proteins ATG-4B (P < .05) and ATG-5 (P < .05) as compared to untreated cardiomyocytes. Doxycycline abrogated MMP activities (P < .0001) and decreased AL-induced autophagy via ATG-5 (P < .05). These in vitro studies demonstrated that doxycycline, in addition to inhibiting MMP, also modulated AL-induced autophagy in cardiomyocytes and provide potential insights for future therapeutic targets for AL-induced proteotoxicity. Novel therapies for cardiotoxicity and heart failure in AL cardiac amyloidosis remain an important unmet need.
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影响因子：
11.1
作者：
Guan J;Mishra S;Qiu Y;Shi J;Trudeau K;Las G;Liesa M;Shirihai OS;Connors LH;Seldin DC;Falk RH;MacRae CA;Liao R
通讯作者：
Liao R
影响因子：
4.6
作者：
Tahir, Usman A.;Doros, Gheorghe;Sam, Flora
通讯作者：
Sam, Flora
影响因子：
2.9
作者：
BOCKER, R;MUHLBERG, W;ESTLER, CJ
通讯作者：
ESTLER, CJ
影响因子：
7.4
作者：
Cardoso I;Martins D;Ribeiro T;Merlini G;Saraiva MJ
通讯作者：
Saraiva MJ
影响因子：
--
作者：
Essick EE;Sam F
通讯作者：
Sam F