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

ABSTRACT

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 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). CONCLUSIONS: 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.