Nitric oxide and calcium signaling regulate myocardial tumor necrosis factor-α expression and cardiac function in sepsisThis article is one of a selection of papers published in this special issue on Calcium Signaling.

Abstract

Myocardial tumor necrosis factor-α (TNF-α), 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-α 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)γ1, and Ca2+signaling pathways. Activation of these pathways increases TNF-α 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-α production through inhibition of ERK1/2 and p38 MAPK activity. Interestingly, endothelial nitric oxide synthase (eNOS) promotes TNF-α expression by enhancing p38 MAPK activation, whereas neuronal NOS (nNOS) inhibits TNF-α production by reducing Ca2+-dependent ERK1/2 activity. Therefore, the JNK1 and nNOS inhibitory pathways represent a “brake” that limits myocardial TNF-α expression in sepsis. Further understanding of these signal transduction mechanisms may lead to novel pharmacological therapies in sepsis.