Abstract 16419: Matrix Metalloproteinase Inhibition Modulates Cardiac Autophagy in Light Chain Cardiac Amyloidosis

• Published in: Circulation (New York, N.Y.) N.Y.), 2018-11, Vol.138 (Suppl_1 Suppl 1), p.A16419-A16419
• Main Authors: Valero-Muñoz, Maria, Wilson, Richard M, Sam, Flora
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539

IntroductionCardiac amyloidosis due to clonal immunoglobulin light chain (LC) is a potentially fatal disease (AL). It is characterized by misfolded LC with extracellular amyloid deposition in the heart resulting in a cardiomyopathy (AL-CMP). Increased matrix metalloproteinase (MMP) activity may contribute to AL-CMP pathogenesis. We previously showed that circulating MMPs are increased in AL-CMP patients. Likewise, recent studies highlighted the role of doxycycline, a non-specific MMP inhibitor, in cardiac proteinopathies, by reducing fibril formation and aggregates in murine models of AL and transthyretin amyloidosis. ObjectiveWe sought to investigate the effect of doxycycline in AL cardiac amyloidosis.MethodsAdult rat ventricular myocytes (ARVMs) were stimulated with either amyloidogenic LC obtained from AL patients (AL; 20 μg/mL) or non-amyloidogenic LC isolated from multiple myeloma patients (control, CT; 20 μg/mL) for 24 hrs. and co-treated with or without doxycycline (DOXY, 50 μg/mL) for 30 min. N=5-6/experiment. ARVM were harvested and MMPs activity was determined by zymography. Since defective autophagy may play a role in AL proteotoxicity, autophagic protein markers were also determined.ResultsAL increased MMP-2 and MMP-9 activity (1.59 and 1.33-fold, P