Modulation of doxorubicin-induced cardiac dysfunction in dominant-negative p38α mitogen-activated protein kinase mice.
Doxorubicin (Dox) is a widely used antitumor drug, but its application is limited because of its cardiotoxic side effects. Increased expression of p38α mitogen-activated protein kinase (MAPK) promotes cardiomyocyte apoptosis and is associated with cardiac dysfunction induced by prolonged agonist stimulation. However, the role of p38α MAPK is not clear in Dox-induced cardiac injury. Cardiac dysfunction was induced by a single injection of Dox into wild-type (WT) mice and transgenic mice with cardiac-specific expression of a dominant-negative mutant form of p38α MAPK (TG). Left ventricular (LV) fractional shortening and ejection fraction were higher and the expression levels of phospho-p38 MAPK and phospho-MAPK-activated mitogen kinase 2 were significantly suppressed in TG mouse heart compared to WT mice after Dox injection. Production of LV proinflammatory cytokines, cardiomyocyte DNA damage, myocardial apoptosis, caspase-3-positive cells, and phospho-p53 expression were decreased in TG mice after Dox injection. Moreover, LV expression of NADPH oxidase subunits and reactive oxygen species was significantly less in TG mice compared to WT mice after Dox injection. These findings suggest that p38α MAPK may play a role in the regulation of cardiac function, oxidative stress, and inflammatory and apoptotic mediators in the heart after Dox administration.
Thandavarayan
Rajarajan A
RA
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
Watanabe
Kenichi
K
Sari
Flori R
FR
Ma
Meilei
M
Lakshmanan
Arun Prasath
AP
Giridharan
Vijayasree V
VV
Gurusamy
Narasimman
N
Nishida
Hiroshi
H
Konishi
Tetsuya
T
Zhang
Shaosong
S
Muslin
Anthony J
AJ
Kodama
Makoto
M
Aizawa
Yoshifusa
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004317:Doxorubicin / Q000008:administration & dosage* / Q000633:toxicity; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D012129:Respiratory Function Tests; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D050505:Mutant Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3