Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, United States of America.
Evans Department of Medicine, Boston University School of Medicine, Boston, MA, United States of America.
Int J Cardiol. 2020 Dec 15;321:133-136. doi: 10.1016/j.ijcard.2020.07.016. Epub 2020 Jul 16.
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.
METHODS/RESULTS: 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.
免疫球蛋白轻链（AL）心脏淀粉样变性的特征是心脏中细胞外淀粉样纤维的沉积，具有潜在的致命性。未经治疗，其临床表现为心力衰竭，病情急剧恶化，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失调有关，基质金属蛋白酶（MMP）水平升高。本通讯提供了多西环素（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的新见解。
方法/结果：用 AL（从心脏淀粉样变性患者中获得）刺激的成年大鼠心室肌细胞增加 MMP-2 和 MMP-9 活性（P<0.05）；自噬标志物微管相关蛋白 1 轻链 3 同工型 II（LC3-II）的表达（P<0.01），以及自噬相关蛋白 ATG-4B（P<0.05）和 ATG-5（P<0.05）均高于未处理的心肌细胞。与未处理的心肌细胞相比，多西环素可阻断 MMP 活性（P<0.0001）并通过 ATG-5 减少 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 外，还可调节心肌细胞中由 AL 诱导的自噬，并为 AL 诱导的蛋白毒性的未来治疗靶点提供潜在的见解。新型疗法治疗 AL 心脏淀粉样变性引起的心脏毒性和心力衰竭仍然是一个重要的未满足需求。
