Nitric oxide and calcium signaling regulate myocardial tumor necrosis factor-α expression and cardiac function in sepsis.
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)gamma1, 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.
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, Lawson Health Research Institute, London, ON N6A 5C1, Canada.
Ting
T
Zhang
Qingping
Q
Feng
D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D005786:Gene Expression Regulation; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D018805:Sepsis / Q000378:metabolism* / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide