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.
Zhang
Ting
T
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, Lawson Health Research Institute, London, ON N6A 5C1, Canada.
Feng
Qingping
Q
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