Sab mediates mitochondrial dysfunction involved in imatinib mesylate-induced cardiotoxicity.
Imatinib mesylate is an effective treatment for chronic myelogenous leukemia and gastrointestinal stromal tumors. Although imatinib mesylate is highly tolerable, it has been implicated in severe congestive heart failure in mouse models and patients. A hallmark of imatinib mesylate-induced cardiotoxicity is mitochondrial dysfunction. The mitochondrial scaffold Sab has been implicated in facilitating signaling responsible for mitochondrial dysfunction in a c-Jun N-terminal Kinase (JNK)-dependent manner. We examined the impact of Sab-mediated signaling on imatinib mesylate cardiotoxicity in H9c2 rat cardiomyocyte-like cells. Silencing Sab increased the LD50of imatinib mesylate 4-fold in H9c2 cells. Disrupting Sab-mediated signaling prevented imatinib mesylate-induced apoptosis as well. Knockdown of Sab or inhibition with a small peptide prevented oxidative stress, which was indicated by decreased reactive oxygen species production, lipid peroxidation, and protein carbonylation. Further, inhibition of Sab-related signaling partially rescued deficits in mitochondrial respiration, ATP production, and membrane potential in imatinib mesylate-treated H9c2 cells. Conversely, over-expression of Sab in H9c2 cells increased the cardiotoxicity of imatinib mesylate in vitro decreasing the LD50over 4-fold. Sab expression was induced in H9c2 cells following cardiovascular-like stress in an AP-1 dependent manner. These data demonstrate that imatinib mesylate influences mitochondrial signaling leading to mitochondrial dysfunction and cardiotoxicity.
Department of Human and Molecular Genetics, Florida International University, Miami, FL 33199, United States; Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, United States.
Tara P
TP
Chambers
Department of Cellular Biology and Pharmacology, Florida International University, Miami, FL 33199, United States.
Luis
L
Santiesteban
Department of Cellular Biology and Pharmacology, Florida International University, Miami, FL 33199, United States.
David
D
Gomez
Department of Cellular Biology and Pharmacology, Florida International University, Miami, FL 33199, United States; Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, United States; Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, United States. Electronic address: jwchambe@fiu.edu.
Jeremy W
JW
Chambers
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D066126:Cardiotoxicity / Q000378:metabolism*; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress; D000068877:Imatinib Mesylate / Q000633:toxicity*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D008840:Microfilament Proteins; D017382:Reactive Oxygen Species; C119201:ponsin; D000068877:Imatinib Mesylate
C-Jun N-terminal Kinase (JNK); Cardiomyocyte; Cell death; Imatinib; Mitochondria; Sab