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

• DOI: 10.1073/pnas.0912263107
• Publication Date: 2010-02-12T03:45:07Z
• Authors: Jianru Shi; Jian Guan; Bingbing Jiang; Daniel A. Brenner; Federica del Monte; Jennifer E. Ward; Lawreen H. Connors; Douglas B. Sawyer; Marc J. Semigran; Thomas E. Macgill...; David C. Seldin; Rodney Falk; Ronglih Liao
• Keywords: Amyloid; Amyloid ; MAPK; Cardiomyocytes; Pyridines; Myocardium; Imidazoles; Apoptosis; Myocardial Contraction; p38 Mitogen-Activated Protein Kinases; 3. Good health; Enzyme Activation; 03 medical and health sciences; 0302 clinical medicine; Humans; Phosphorylation; Protein Kinase Inhibitors

Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy a median survival of less than 8 months and 5-year <10%. Contributing to this poor prognosis is the fact that these patients generally do not tolerate standard heart failure therapies. The molecular mechanisms underlying deadly form disease remain unclear. Although interstitial amyloid fibril deposition Ig light chain proteins major cause dysfunction in AL amyloidosis, we have previously shown precursor directly impair function at cellular isolated organ levels, independent formation. In study, report amyloidogenic (AL-LC) provoke oxidative stress, dysfunction, apoptosis adult cardiomyocytes through activation p38 mitogen-activated protein kinase (MAPK). AL-LC–induced was found be upstream MAPK kinase, MKK3/6, instead depends upon transforming growth factor-β-activated kinase-1 binding protein-1 (TAB1)-mediated p38α autophosphorylation. Treatment SB203580, selective inhibitor, significantly attenuated apoptosis. Our data provide unique mechanistic insight into pathogenesis AL-LC toxicity suggest TAB1-mediated autophosphorylation may serve as an important event leading subsequent failure.