Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway

Shi, Jianru; Guan, Jian; Jiang, Bingbing; Brenner, Daniel; Monte, Federica del; Ward, Jennifer E.; Connors, Lawreen H.; Sawyer, Douglas B.; Semigran, Marc J.; MacGillivray, Thomas E.; Seldin, David C.; Falk, Rodney H.; Liao, Ronglih

doi:10.1073/pnas.0912263107

Cited by 274 publications

(220 citation statements)

References 27 publications

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“…The observation that changes in serum FLC concentration are paralleled by concordant and proportional variations of NT-proBNP, reflecting improvement or worsening of heart dysfunction even in the absence of changes in cardiac amyloid load (estimated by echocardiography) [19,92], lead to hypothesize a significant pathogenetic role of soluble light chain species. This evidence confirms experimental observations obtained in vitro [123][124][125] and indicates that cardiac damage in amyloidosis results from the sum of multiple factors; in particular, direct toxicity of soluble cardiotoxic FLC towards cardiac cells significantly contributes to the overall dysfunction, along with the anatomical/mechanical damage due to deposition of the stable amyloid fibrils.…”

Section: Biomarkers In Assessment Of Amyloid Organ Dysfunctionsupporting

confidence: 77%

Biochemical markers in early diagnosis and management of systemic amyloidoses

Lavatelli

Albertini

Fonzo

et al. 2014

Clinical Chemistry and Laboratory Medicine (CCLM)

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Systemic amyloid diseases are characterized by widespread protein deposition as amyloid fibrils. Precise diagnostic framing is the prerequisite for a correct management of patients. This complex process is achieved through a series of steps, which include detection of the tissue amyloid deposits, identification of the amyloid type, demonstration of the amyloidogenic precursor, and evaluation of organ dysfunction/damage. Laboratory medicine plays a central role in the diagnosis and management of systemic amyloidoses, through the quantification of the amyloidogenic precursor and evaluation of end-organ damage using biomarkers.

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Section: Biomarkers In Assessment Of Amyloid Organ Dysfunctionsupporting

confidence: 77%

Biochemical markers in early diagnosis and management of systemic amyloidoses

Lavatelli

Albertini

Fonzo

et al. 2014

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…Soluble monoclonal LC, isolated from patients with amyloidosis, can impair rat cardiomyocyte function (11) and induce apoptotic events in mouse cardiomyocytes (12,13). Also, urinederived LC can be internalized into primary rat cardiac fibroblasts (14) and primary human renal mesangial cells (15) through a pinocytic pathway (16) or via receptor, clathrin-mediated mechanisms, respectively (15).…”

Section: Light Chain (Al)mentioning

confidence: 99%

“…Amyloid fibrils have been considered to play a secondary role in cell toxicity, yielding the toxic role to the soluble species (12,13,53). LC fibrillary species were not considered in the toxicity landscape of AL amyloidosis until recently (24).…”

Section: Journal Of Biological Chemistry 19819mentioning

confidence: 99%

Cell Damage in Light Chain Amyloidosis

Argany¹,

Lin²,

Misra³

et al. 2016

Journal of Biological Chemistry

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Light chain (AL) amyloidosis is an incurable human disease characterized by the misfolding, aggregation, and systemic deposition of amyloid composed of immunoglobulin light chains (LC). This work describes our studies on potential mechanisms of AL cytotoxicity. We have studied the internalization of AL soluble proteins and amyloid fibrils into human AC16 cardiomyocytes by using real time live cell image analysis. Our results show how external amyloid aggregates rapidly surround the cells and act as a recruitment point for soluble protein, triggering the amyloid fibril elongation. Soluble protein and external aggregates are internalized into AC16 cells via macropinocytosis. AL amyloid fibrils are shown to be highly cytotoxic at low concentrations. Additionally, caspase assays revealed soluble protein induces apoptosis, demonstrating different cytotoxic mechanisms between soluble protein and amyloid aggregates. This study emphasizes the complex immunoglobulin light chain-cell interactions that result in fibril internalization, protein recruitment, and cytotoxicity that may occur in AL amyloidosis. Light chain (AL)2 amyloidosis is a protein misfolding disease characterized by extracellular deposition of immunoglobulin light chains (LC) as amyloid fibrils. LC proteins are comprised of two distinct domains: the variable (V L ) and constant (C L ) domains (also called LC full-length (FL) protein to differentiate with the V L domain). In patients with AL amyloidosis, the LC aggregate and deposit in vital organs, causing organ failure and death (1). The factors governing deposition in individual tissues are unknown. Patients with cardiac AL amyloidosis have the worst prognosis, with a median survival of less than a year (2, 3).The finding that the V L was the primary component of amyloid fibrils influenced previous biophysical studies (4,5). Recent proteomic studies have demonstrated that amyloid deposits are likely heterogeneous in nature and can be formed by FL, V L , C L , or mixtures of all types of LC fragments (6 -8). Thermodynamic studies proposed a stabilizing role for the 3C L domain in the stability and a modulating effect on fibril formation (9). Recently, our laboratory has demonstrated that the C L domain modulates the amyloid formation reaction but has no effect on the stability of the protein (10).Soluble monoclonal LC, isolated from patients with amyloidosis, can impair rat cardiomyocyte function (11) and induce apoptotic events in mouse cardiomyocytes (12, 13). Also, urinederived LC can be internalized into primary rat cardiac fibroblasts (14) and primary human renal mesangial cells (15) through a pinocytic pathway (16) or via receptor, clathrin-mediated mechanisms, respectively (15).Within the amyloid field, it is widely accepted that oligomeric species are potentially more toxic than mature fibrils (17-20). However, toxicity associated with amyloid fibrils may also be pathologically relevant. Engel et al. (21) described a mechanism in which growth of islet amyloid associated polypeptides fibrils is re...

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“…This observation may be due to the direct cytotoxic nature of free LC proteins on cardiomyocytes as previously observed. 16,17 Alternatively, CLU may be internalized through the cell surface receptor megalin. Immunohistochemical results were consistent in all nine amyloid tissues that were analyzed; the results obtained on additional tissues (not shown in Figure 1 (Figure 1M).…”

Section: Cardiac Amyloid Deposits Contain Clusterinmentioning

confidence: 99%

Evidence for a Functional Role of the Molecular Chaperone Clusterin in Amyloidotic Cardiomyopathy

Greene

Sam

Hoo

et al. 2011

The American Journal of Pathology

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Molecular chaperones, including the extracellular protein clusterin (CLU), play a significant role in maintaining proteostasis; they have a unique capacity to bind and stabilize non-native protein conformations, prevent aggregation, and keep proteins in a soluble foldingcompetent state. In this study, we investigated amyloidinfiltrated cardiac tissue for the presence of CLU and measured serum levels of CLU in patients with and without amyloidotic cardiomyopathy (CMP). Cardiac tissues containing amyloid deposits composed of either transthyretin (TTR) or Ig light chain from nine patients with amyloidotic CMP were examined for the presence of CLU using immunohistochemical techniques. CLU staining coincided with the extracellular myocardial amyloid deposits in tissues from patients with familial TTR, senile systemic, and Ig light chain amyloidosis. The association of CLU with cardiac amyloid deposits was confirmed by immunogold electron microscopy. Serum concentrations of CLU were measured in familial TTR, senile systemic, and Ig light chain amyloidosis patient groups and compared with both age-matched healthy controls and with patients with CMP unrelated to amyloid disease. Subset analysis of disease cohorts, based on cardiac involvement, indicated that decreased serum CLU concentrations were associated with amyloidotic CMP. Taken together, these results suggest that CLU may play a pathogenetic role in TTR and Ig light chain amyloidoses and amyloidotic CMP.

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Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway

Cited by 274 publications

References 27 publications

Biochemical markers in early diagnosis and management of systemic amyloidoses

Biochemical markers in early diagnosis and management of systemic amyloidoses

Cell Damage in Light Chain Amyloidosis

Evidence for a Functional Role of the Molecular Chaperone Clusterin in Amyloidotic Cardiomyopathy

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