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Chronic isoproterenol stimulation induces cardiomyocyte apoptosis through p38‐cytokine‐iNOS pathway
Author(s) -
Jiao Xiangying,
Hu Aihua,
Tao Ling,
Lopez Bernard,
Christopher Theodore,
Sun Jianzhong,
Ma Xin L
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1375-c
Subject(s) - nitrotyrosine , apoptosis , tunel assay , stimulation , p38 mitogen activated protein kinases , cytokine , endocrinology , medicine , chemistry , pharmacology , mapk/erk pathway , signal transduction , nitric oxide , nitric oxide synthase , biochemistry
A prolonged release or sudden surge of catecholamine, as seen in major surgery, trauma, sepsis, can increases the patient’s risk for myocardial ischemia and infarction. In this study, we used isoproterenol (ISO) to determine whether chronic adrenoreceptor activation can induce cardiac injury, and if so, to investigate mechanism involved. Adult male mice were randomly selected to receive vehicle, ISO (30mg/kg/d), ISO+1400W (iNOS inhibitor, 2mg/kg/d) or ISO+SB203580 (p38 MAPK inhibitor,20mg/kg/d) via an osmotic pump implanted subcutaneously for 7 days, and heart tissue and plasma were collected for further assays. Chronic ISO stimulation induced marked cardiomyocyte apoptosis as evidenced by TUNEL and caspase‐3 activity and also increased plasma cytokine (IL‐6: 43.2±18.9 vs. 11.7±2.6 pg/ml, TNF‐α 11.1±1.5 vs. 8.4±1.0 pg/ml, p<0.01), cardiac iNOS expression, nitrotyrosine content (4.2±0.7 vs. 2.3±0.6 nmol/g protein, p<0.01) and p38 MAPK activation. Pretreatment with 1400W reduced ISO‐induced ONOO − production and cardiomyocyte apoptosis, but failed to block cytokine production and p38 activation. However, pretreatment with SB203580 inhibited ISO‐induced cytokine production, blocked cardiac iNOS expression and ONOO − formation and attenuated cardiomyocyte apoptosis. These results indicate that chronic ISO stimulation can induce cardiomyocyte death through a p38 MAPK initialed, ONOO − ‐mediated signaling pathway.