title: Crosstalk between leptin and interleukin-1β abrogates negative inotropic effects in a model of chronic hyperleptinemia.
abstract: Interleukin 1 beta (IL-1β) is a proinflammatory cytokine with potent cardiosuppressive effects. Previous studies have shown that leptin blunts the negative inotropic effects of IL-1β in isolated adult rat cardiac myocytes. However, the interactions between leptin and IL-1β in the heart have not been examined on a background of chronic hyperleptinemia. To study this interaction, we have chosen the SHHF rat, a model of spontaneous hypertension that ultimately develops congestive heart failure. SHHF that are heterozygous for a null mutation of the leptin receptor (+/fa(cp), HET) are phenotypically lean but chronically hyperleptinemic and develop heart failure earlier than their normoleptinemic true lean (+/+, LN) littermates. Simultaneous cell shortening and calcium transients were measured in isolated ventricular cardiac myocytes from LN and HET SHHF in response to leptin, IL-1β or IL-1β following one hour pretreatment with leptin. Despite evidence of metabolic leptin resistance, HET myocytes were sensitive to the negative inotropic effect of leptin, similar to LN. Contractility returned to control levels in myocytes from HET that were pretreated with leptin prior to IL-1β, while contractility remained depressed compared with control and similar to leptin alone in LN. Chronic hyperleptinemia resulted in altered JAK/STAT signaling in response to leptin and IL-1β in isolated perfused hearts from HET compared with LN SHHF. Phosphorylated STAT3 (pSTAT3) and STAT5 (pSTAT5) decreased when HET hearts were treated with leptin followed by IL-1β. While decreases in pSTAT3 and pSTAT5 may be associated with abrogation of the acute negative inotropic effects of IL-1β in the presence of leptin in HET, long-term consequences remain to be explored. This study demonstrates that the heart remains sensitive to leptin in a hyperleptinemic state. Crosstalk between leptin and IL-1β can influence cardiac function and cytokine signaling and these interactions are moderated by the presence of long-term hyperleptinemia.
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210, USA. radin.1@osu.edu
authors.forename: M Judith
authors.initials: MJ
authors.lastname: Radin
authors.forename: Bethany J
authors.initials: BJ
authors.lastname: Holycross
authors.forename: Sylvia A
authors.initials: SA
authors.lastname: McCune
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Altschuld
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006973:Hypertension / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D020738:Leptin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D054411:Receptors, Leptin / Q000235:genetics; D015398:Signal Transduction
chemical_list: D053583:Interleukin-1beta; D020738:Leptin; D054411:Receptors, Leptin