Nitric oxide and calcium signaling regulate myocardial tumor necrosis factor-α expression and cardiac function in sepsis

被引:22
|
作者
Zhang, Ting [1 ]
Feng, Qingping [1 ]
机构
[1] Univ Western Ontario, Dept Physiol & Pharmacol, Schulich Sch Med & Dent, Lawson Hlth Res Inst, London, ON N6A 5C1, Canada
基金
加拿大健康研究院;
关键词
sepsis; cardiac dysfunction; tumor necrosis factor-alpha; nitric oxide; calcium; signal transduction; NF-KAPPA-B; NEONATAL MOUSE CARDIOMYOCYTES; ADULT FELINE MYOCARDIUM; PROTEIN-KINASE-C; TNF-ALPHA; P38; MAPK; PHOSPHOLIPASE-C; NADPH OXIDASE; SEPTIC SHOCK; GENE-EXPRESSION;
D O I
10.1139/Y09-097
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Myocardial tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, is a critical inducer of myocardial dysfunction in sepsis. The purpose of this review is to summarize the mechanisms through which TNF-alpha production is regulated in cardiomyocytes in response to lipopolysaccharide (LPS), a key pathogen-associated molecular pattern (PAMP) in sepsis. These mechanisms include Nox2-containing NAD(P)H oxidase, phospholipase C (PLC)gamma 1, and Ca2+ signaling pathways. Activation of these pathways increases TNF-alpha expression via activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK). Conversely, activation of c-Jun NH2-terminal kinase 1 (JNK1) negatively regulates TNF-alpha production through inhibition of ERK1/2 and p38 MAPK activity. Interestingly, endothelial nitric oxide synthase (eNOS) promotes TNF-alpha expression by enhancing p38 MAPK activation, whereas neuronal NOS (nNOS) inhibits TNF-alpha production by reducing Ca2+-dependent ERK1/2 activity. Therefore, the JNK1 and nNOS inhibitory pathways represent a "brake" that limits myocardial TNF-alpha expression in sepsis. Further understanding of these signal transduction mechanisms may lead to novel pharmacological therapies in sepsis.
引用
收藏
页码:92 / 104
页数:13
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