Doxycycline decreases amyloidogenic light chain-induced autophagy in isolated primary cardiac myocytes

[摘要] Background: 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 ventricularmyocytes stimulatedwith AL (obtained fromcardiac 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 b.0001) and decreased AL-induced autophagy via ATG-5 (P <.05). Conclusions: These in vitro studies demonstrated that doxycycline, in addition to inhibitingMMP, alsomodulated 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. (C) 2020 Elsevier B.V. All rights reserved.

[发布日期] 2020-12-15

[关键词] Light chain cardiac amyloidosis;Cardiomyocytes;Matrix metalloproteinases