Abstract 16784: Doxycycline Modulates Cardiomyocyte Remodeling in Light Chain-Induced Cardiac Amyloidosis
Cardiac amyloidosis due to clonal immunoglobulin light chain (AL) is a potentially fatal disease. The mechanism(s) of cardiac dysfunction and myocardial damage caused by amyloid fibrils deposition represents the least understood aspect of amyloid pathology. Once diagnosed with heart failure (HF), the median survival of AL cardiac amyloidosis (ALCMP) patients is <6months if left untreated. However, only a minority of ALCMP patients are eligible for definitive therapy which includes autologous stem cell transplant and high dose melphalan. Despite this most patients continue to have evidence of HF and marked LVH on echocardiogram without regression even when this aggressive regimen is successful. Extracellular matrix turnover is implicated in the pathogenesis of ALCMP. Increased matrix metalloproteinase (MMP) activity may contribute to ALCMP. Doxycycline (DOX), an MMP inhibitor, reduces fibril formation and aggregates in murine models of AL and TTR amyloidosis. Autophagy plays a role in adverse cardiac remodeling, but it is unknown if LC deposition causes cardiomyocyte autophagy. We sought to test the hypothesis that DOX modulates LC-induced cardiac dysfunction and whether autophagy is part of the pathogenesis of the disease. Isolated adult rat cardiomyocytes were exposed to AL-LC (20μg/mL) or control LC (20μg/mL). MMP activities, proteins and intracellular signaling molecule expressions were measured. AL-LC increased MMP-2 (28±8%) and MMP-9 (25±6% P<0.05 for both) activities. U0126, a MEK/ERK inhibitor, blocked these increases, suggesting that the MAPK pathway is involved. DOX also decreased MMP-9 (-35±6%) and MMP-2 (-35±6% P<0.001 for both) activities vs AL-LC alone. AL-LC increased LC3II:LC3I protein expression ratio by 112±11% and ROS-regulated ATG4B expression by 156±13% (P<0.05 vs control for both). DOX decreased AL-LC induced LC3II:LC3I ratio by 42±8% (P=0.05) but did not significantly modulate ATG4B expression vs AL-LC. Thus, AL-LC induces autophagy and MMP-2 and MMP-9 activities in cardiomyocytes, which is modulated by DOX via a MEK/ERK pathway. Since ATG4B is not involved it may be independent of ROS. These pathways may provide potential targets for future therapeutic interventions for this near fatal form of cardiomyopathy.
Author Disclosures: R.M. Wilson: None. D.C. Seldin: None. F. Sam: None.
- © 2014 by American Heart Association, Inc.