Leptin modulates the negative inotropic effect of interleukin-1β in cardiac myocytes

Abstract

Interleukin-1beta (IL-1beta) is a potent negative inotrope implicated in the functional abnormalities of heart failure. Because the adipokine, leptin, protects against some of the cardiovascular effects of endotoxin, we hypothesized that leptin may modulate the cardiosuppressive effects of IL-1beta in isolated cardiomyocytes. Ventricular cardiac myocytes isolated from adult male Sprague Dawley rats were analyzed simultaneously for electrically stimulated contractility and calcium transients following 30 min exposure to IL-1beta (10 ng/ml) with or without 60 min pretreatment with leptin (25 ng/ml). IL-1beta decreased cell shortening, depressed maximal velocities of shortening and relengthening, and prolonged the time to 90% relaxation. The change in fura2-AM fluorescence ratio amplitude (Delta[Ca(2+)]) was significantly depressed and the time to return to baseline [Ca(2+)] was prolonged. The negative inotropic effects of IL-1beta were blocked by the neutral sphingomyelinase inhibitor Manumycin A (5 microM) or the ceramidase inhibitor N-oleoyl ethanolamine (1 microM). Prior exposure of myocytes to leptin blocked IL-1beta-induced cardiosuppression in conjunction with a blunting of IL-1beta stimulated ceramide accumulation. These data suggest that leptin may modulate IL-1beta signaling through the sphingolipid signaling pathway in cardiomyocytes.

Secretory products of guinea pig epicardial fat induce insulin resistance and impair primary adult rat cardiomyocyte function

“…Therefore, it seems unlikely that an increased utilization of lactate as myocardial energy substrate, which negatively affects myocardial performance [34], contributes to the observed effects caused by CM-EAT from HFD-fed animals. In support of previous studies, which have ascribed cardiosuppressive effects to adipokines [17,[35][36][37][38], like FABP4, IL1␤, IL6 and TNF-␣, boiling was found to destroy the detrimental effect of CM on cardiomyocyte function. Therefore, the CM were evaluated for diet-induced alterations in adipokine secretion by EAT and SAT.…”

Targeting Interleukin-1 in Heart Disease

“…In vitro studies describe impaired relaxation of cardiomyocytes. 92, 102 In our own laboratory, we have observed that a single injection of recombinant murine IL-1β (3 mcg/kg) in healthy adult mice leads to an increase in left ventricular end diastolic pressure (4 mmHg in controls vs 8 mmHg in IL-1β-treated mice) accompanied by an overall reduction in contractility and relaxation, measured as +dP/dT and –dP/dT, and an increase in isovolumetric relaxation measured at Doppler echocardiography (personal communication by the authors).…”

Cardiac and Metabolic Variables in Obese Dogs

“…Adipokines produced by adipose tissue, such as leptin and adiponectin, peripheral endocrine substrates such as insulin and glucagon, as well as central pathways including the leptin‐melanocortin system influence metabolism in obese patients. Hypoadiponectinemia, hyperleptinemia, and leptin resistance previously have been identified in both obese people and dogs . These metabolic derangements can result in cardiac dysfunction as a consequence of altered cardiac mitochondrial metabolism and result in localized cardiac insulin resistance and intramyocardial lipid accumulation …”