María Valero-Muñoz1, Richard M Wilson1, Rosa Bretón-Romero1, Dominique Croteau1, David C Seldin2, Flora Sam3. 1. Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, United States of America. 2. Evans Department of Medicine, Boston University School of Medicine, Boston, MA, United States of America. 3. Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, United States of America; Cardiovascular Section, 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. Electronic address: florasam@bu.edu.
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.
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.
Authors: Mary K Rude; Toni-Ann S Duhaney; Gabriela M Kuster; Sharon Judge; Joline Heo; Wilson S Colucci; Deborah A Siwik; Flora Sam Journal: Hypertension Date: 2005-07-25 Impact factor: 10.190
Authors: Usman A Tahir; Gheorghe Doros; John S Kim; Lawreen H Connors; David C Seldin; Flora Sam Journal: Sci Rep Date: 2019-06-12 Impact factor: 4.379
Authors: Komei Tanaka; Eric E Essick; Gheorghe Doros; Kahraman Tanriverdi; Lawreen H Connors; David C Seldin; Flora Sam Journal: J Am Heart Assoc Date: 2013-03-12 Impact factor: 5.501