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

Published on Dec 15, 2020in International Journal of Cardiology3.229
· DOI :10.1016/J.IJCARD.2020.07.016
María Valero-Muñoz12
Estimated H-index: 12
(BU: Boston University),
Richard M. Wilson11
Estimated H-index: 11
(BU: Boston University)
+ 3 AuthorsFlora Sam37
Estimated H-index: 37
(BU: Boston University)
Sources
Abstract
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 Methods/results Adult rat ventricular myocytes stimulated with AL (obtained from cardiac amyloidosis patients) increased MMP-2 and MMP-9 activities (P  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.
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Cardiac involvement in systemic amyloidosis (AL) occurs in ~50% of all AL patients. However once symptomatic heart failure develops, therapeutic options are limited thereby conferring a poor overall prognosis. The median survival is <6 months when AL patients are untreated for the underlying plasma cell dyscrasia. We thus sought to identify risk factors of increased mortality in treatment-naive, AL cardiac amyloidosis with heart failure. Patients with biopsy-proven AL cardiac amyloid, who presen...
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Autophagy is a highly conserved process that degrades certain intracellular contents in both physiological and pathological conditions. Autophagy-related proteins (ATG) are key players in this pathway, among which ATG5 is indispensable in both canonical and non-canonical autophagy. Recent studies demonstrate that ATG5 modulates the immune system and crosstalks with apoptosis. However, our knowledge of the pathogenesis and regulatory mechanisms of autophagy in various immune related diseases is l...
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#1Le Zhang (SJTU: Shanghai Jiao Tong University)H-Index: 7
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ABSTRACTExperimental evidence suggest that breast tumors originate from breast cancer stem cells (BCSCs), and that mitochondrial biogenesis is essential for the anchorage-independent clonal expansion and survival of CSCs, thus rendering mitochondria a significant target for novel treatment approaches. One of the recognized side effects of the FDA-approved drug, doxycycline is the inhibition of mitochondrial biogenesis. Here we investigate the mechanism by which doxycycline exerts its inhibitory ...
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#1Ashutosh D. Wechalekar (UCL: University College London)H-Index: 58
#2Carol J. Whelan (UCL: University College London)H-Index: 30
Encouraging impact of doxycycline on early mortality in cardiac light chain (AL) amyloidosis
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#1Rodney H. FalkH-Index: 81
#2Kevin M. Alexander (Brigham and Women's Hospital)H-Index: 10
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Abstract The amyloidoses are a group of protein-folding disorders in which ≥1 organ is infiltrated by proteinaceous deposits known as amyloid. The deposits are derived from 1 of several amyloidogenic precursor proteins, and the prognosis of the disease is determined both by the organ(s) involved and the type of amyloid. Amyloid involvement of the heart (cardiac amyloidosis) carries the worst prognosis of any involved organ, and light-chain (AL) amyloidosis is the most serious form of the disease...
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Objectives. Numerous loci were identified to perturb gene expression in trans. As elevated ATG5 expression was observed in systemic lupus erythematosus (SLE), the study was conducted to analyze the genome-wide genetic regulatory mechanisms associated with ATG5 expression in a Chinese population with lupus nephritis (LN). Methods. The online expression quantitative trait loci database was searched for trans-expression single nucleotide polymorphisms (trans-eSNPs) of ATG5. Tagging trans-eSNPs were...
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#1Jian Guan (Brigham and Women's Hospital)H-Index: 15
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AL amyloidosis is the consequence of clonal production of amyloidogenic immunoglobulin light chain (LC) proteins, often resulting in a rapidly progressive and fatal amyloid cardiomyopathy. Recent work has found that amyloidogenic LC directly initiate a cardiotoxic response underlying the pathogenesis of the cardiomyopathy; however, the mechanisms that contribute to this proteotoxicity remain unknown. Using human amyloidogenic LC isolated from patients with amyloid cardiomyopathy, we reveal that ...
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Background Cardiac amyloidosis due to amyloid fibril deposition in the heart results in cardiomyopathy (CMP) with heart failure (HF) and/or conduction disturbances. Immunoglobulin light chain–related CMP (AL-CMP) features rapidly progressive HF with an extremely poor prognosis compared with a CMP due to the deposition of mutant (ATTR) amyloidosis or wild-type (senile systemic amyloidosis, SSA) transthyretin (TTR) proteins. Amyloid fibril deposition disrupts the myocardial extracellular matrix (E...
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