Increased myocardial oxygen consumption by TNF-α is mediated by a sphingosine signaling pathway

Abstract

The present study investigated the effect of tumor necrosis factor (TNF)-␣ on myocardial energy metabolism as estimated by myocardial oxygen consumption (MV O2). MV O2 of electrically stimulated isolated trabeculae of right ventricular Wistar rat myocardium was analyzed using a Clark-type oxygen probe. After the initial data collection in the absence of TNF-␣, measurements were repeated after TNF-␣ stimulation. In separate experiments, pretreatment with the nitric oxide (NO) synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME) or the ceramidase inhibitor n-oleoylethanolamine (NOE) was done to investigate NO/sphingosine-related effects. TNF-␣ impaired myocardial economy at increasing stimulation frequencies without altering baseline MV O2. Incubation with TNF-␣ in the presence of L-NAME further impaired myocardial economy. NOE preincubation abrogated the TNF-␣ effect on myocardial economy. Moreover, the negative inotropic effect of TNF-␣ was observed in NOE-pretreated but not L-NAME-pretreated muscle fibers. Exogenous sphingosine mimicked the TNF-␣ effect on mechanics and energetics. We conclude that TNF-␣ impairs the economy of chemomechanical energy transduction primarily through a sphingosine-mediated pathway. cytokines; nitric oxide; myocardial energy metabolism; tumor necrosis factor-␣

Toll-like receptor and its roles in myocardial ischemic/reperfusion injury

“…Clinical research data establishes that increased levels of IL-6 are associated with cardiac dysfunction after CPB [118]. IL-6 is a multifunction cytokine produced by different cell types, and is reported to serve as a direct cardiodepressant, inhibiting contractility in the hamster myocardium [119]. The primary mechanism of IL-6-mediated myocardial contractility inhibition is shown by reduced peak systolic intracellular Ca + transient levels, increased iNOS-induced NO production, and, subsequently, decreased levels of cGMP-mediated L-type Ca + -channel [119–121].…”

“…IL-6 is a multifunction cytokine produced by different cell types, and is reported to serve as a direct cardiodepressant, inhibiting contractility in the hamster myocardium [119]. The primary mechanism of IL-6-mediated myocardial contractility inhibition is shown by reduced peak systolic intracellular Ca + transient levels, increased iNOS-induced NO production, and, subsequently, decreased levels of cGMP-mediated L-type Ca + -channel [119–121]. In addition, IL-6 induces activation and production of diverse chemoattractants, intercellular adhesion molecules (ICAM) and complements, as well as C-reactive protein (CRP), which is an acute phase protein produced by the liver.…”

Cytokine-Induced Modulation of Cardiac Function

“…The importance of sphingolipid-dependent signaling in the genesis of TNF-␣-mediated myocardial dysfunction has been further confirmed in studies of adult guinea pig myocytes, 75 isolated rat 65,78,81 and rabbit 3 hearts, and rat right ventricular trabeculae. 66 Studies evaluating the role of sphingolipids in the mechanical effects of other proinflammatory cytokines are few. In a study of human atrial trabeculae, inhibition of either sphingosine generation or NO release prevented the early (and delayed) negative inotropic effects of TNF-␣ and IL-1␤, either alone or in combination.…”

Proinflammatory Cytokines Mediate GPCR Dysfunction

“…Studies have documented that pro-inflammatory cytokines modulate contractile function and these effects can be classified into immediate and delayed effects. The immediate effects of pro-inflammatory cytokines are identified to be on EC coupling 19, 28–40 , on nitric oxide production by NOS 65–82 , on Sphingomyelinase-dependent signaling 56, 71, 74, 76, 81–95 , and/or on phospholipase A2 (PLA2) and arachidonic acid (AA) activation 85, 96–102 . In contrast, to these immediate effects, delayed effects that play a key role in modulating contractile function include altered βAR signaling and loss of βAR responsiveness to its cognate βAR agonist like isoproterenol 10, 71, 103, 104 .…”