title: Palmitate promotes inflammatory responses and cellular senescence in cardiac fibroblasts.
abstract: Palmitate triggers inflammatory responses in several cell types, but its effects on cardiac fibroblasts are at present unknown. The aims of the study were to (1) assess the potential of palmitate to promote inflammatory signaling in cardiac fibroblasts through TLR4 and the NLRP3 inflammasome and (2) characterize the cellular phenotype of cardiac fibroblasts exposed to palmitate. We examined whether palmitate induces inflammatory responses in cardiac fibroblasts from WT, NLRP3-/-and ASC-/-mice (C57BL/6 background). Exposure to palmitate caused production of TNF, IL-6 and CXCL2 via TLR4 activation. NLRP3 inflammasomes are activated in a two-step manner. Whereas palmitate did not prime the NLRP3 inflammasome, it induced activation in LPS-primed cardiac fibroblasts as indicated by IL-1β, IL-18 production and NLRP3-ASC co-localization. Palmitate-induced NLRP3 inflammasome activation in LPS-primed cardiac fibroblasts was associated with reduced AMPK activity, mitochondrial reactive oxygen species production and mitochondrial dysfunction. The cardiac fibroblast phenotype caused by palmitate, in an LPS and NLRP3 independent manner, was characterized by decreased cellular proliferation, contractility, collagen and MMP-2 expression, as well as increased senescence-associated β-galactosidase activity, and consistent with a state of cellular senescence. This study establishes that in vitro palmitate exposure of cardiac fibroblasts provides inflammatory responses via TLR4 and NLRP3 inflammasome activation. Palmitate also modulates cardiac fibroblast functionality, in a NLRP3 independent manner, resulting in a phenotype related to cellular senescence. These effects of palmitate could be of importance for myocardial dysfunction in obese and diabetic patients.
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway; KG Jebsen Center for Inflammation Research, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway.
authors.forename: Marina
authors.initials: M
authors.lastname: Sokolova
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Center for Heart Failure Research, University of Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Norway; Department of Medicine, Diakonhjemmet Hospital, Oslo, Norway.
authors.forename: Leif Erik
authors.initials: LE
authors.lastname: Vinge
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; KG Jebsen Center for Inflammation Research, University of Oslo, Norway.
authors.forename: Katrine
authors.initials: K
authors.lastname: Alfsnes
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway; KG Jebsen Center for Inflammation Research, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway.
authors.forename: Maria Belland
authors.initials: MB
authors.lastname: Olsen
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital Rikshospitalet, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Eide
authors.affiliation: Center for Heart Failure Research, University of Oslo, Norway; Institute of Surgical Research, Oslo University Hospital Rikshospitalet, Norway.
authors.forename: Ole Jørgen
authors.initials: OJ
authors.lastname: Kaasbøll
authors.affiliation: Center for Heart Failure Research, University of Oslo, Norway; Institute of Surgical Research, Oslo University Hospital Rikshospitalet, Norway.
authors.forename: Håvard
authors.initials: H
authors.lastname: Attramadal
authors.affiliation: Center for Heart Failure Research, University of Oslo, Norway; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: May-Kristin
authors.initials: MK
authors.lastname: Torp
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; KG Jebsen Center for Inflammation Research, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway; Department of Medicine, Diakonhjemmet Hospital, Oslo, Norway.
authors.forename: Linn E
authors.initials: LE
authors.lastname: Fosshaug
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; KG Jebsen Center for Inflammation Research, University of Oslo, Norway.
authors.forename: Azita
authors.initials: A
authors.lastname: Rashidi
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA; Centre of Molecular Inflammation Research, NTNU, Trondheim, Norway.
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; KG Jebsen Center for Inflammation Research, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway.
authors.forename: Alexandra Vanessa
authors.initials: AV
authors.lastname: Finsen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; KG Jebsen Center for Inflammation Research, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Sandanger
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway; KG Jebsen Center for Inflammation Research, University of Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway; KG Jebsen Center for Inflammation Research, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway.
authors.forename: Trine
authors.initials: T
authors.lastname: Ranheim
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway; KG Jebsen Center for Inflammation Research, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway. Electronic address: arne.yndestad@rr-research.no.
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects*; D054426:Chemokine CXCL2 / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D054426:Chemokine CXCL2; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010168:Palmitates; D051197:Toll-Like Receptor 4; D001616:beta-Galactosidase
keywords: Cardiac fibroblast; Cellular senescence; Inflammation; NLRP3; Palmitate; TLR4