title: NOD1 activation induces cardiac dysfunction and modulates cardiac fibrosis and cardiomyocyte apoptosis.
abstract: The innate immune system is responsible for the initial response of an organism to potentially harmful stressors, pathogens or tissue injury, and accordingly plays an essential role in the pathogenesis of many inflammatory processes, including some cardiovascular diseases. Toll like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLRs) are pattern recognition receptors that play an important role in the induction of innate immune and inflammatory responses. There is a line of evidence supporting that activation of TLRs contributes to the development and progression of cardiovascular diseases but less is known regarding the role of NLRs. Here we demonstrate the presence of the NLR member NOD1 (nucleotide-binding oligomerization domain containing 1) in the murine heart. Activation of NOD1 with the specific agonist C12-iEDAP, but not with the inactive analogue iE-Lys, induces a time- and dose-dependent cardiac dysfunction that occurs concomitantly with cardiac fibrosis and apoptosis. The administration of iEDAP promotes the activation of the NF-κB and TGF-β pathways and induces apoptosis in whole hearts. At the cellular level, both native cardiomyocytes and cardiac fibroblasts expressed NOD1. The NLR activation in cardiomyocytes was associated with NF-κB activation and induction of apoptosis. NOD1 stimulation in fibroblasts was linked to NF-κB activation and to increased expression of pro-fibrotic mediators. The down-regulation of NOD1 by specific siRNAs blunted the effect of iEDAP on the pro-fibrotic TGF-β pathway and cell apoptosis. In conclusion, our report uncovers a new pro-inflammatory target that is expressed in the heart, NOD1. The specific activation of this NLR induces cardiac dysfunction and modulates cardiac fibrosis and cardiomyocyte apoptosis, pathological processes involved in several cardiac diseases such as heart failure.
authors.affiliation: TumorImmunology Lab, Instituto de Investigación Hospital La Paz, Madrid, Spain. mvelasco@iib.uam.es
authors.forename: María
authors.initials: M
authors.lastname: Fernández-Velasco
authors.forename: Patricia
authors.initials: P
authors.lastname: Prieto
authors.forename: Verónica
authors.initials: V
authors.lastname: Terrón
authors.forename: Gemma
authors.initials: G
authors.lastname: Benito
authors.forename: Juana M
authors.initials: JM
authors.lastname: Flores
authors.forename: Carmen
authors.initials: C
authors.lastname: Delgado
authors.forename: Carlos
authors.initials: C
authors.lastname: Zaragoza
authors.forename: Begoña
authors.initials: B
authors.lastname: Lavin
authors.forename: Mónica
authors.initials: M
authors.lastname: Gómez-Parrizas
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Collazo
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001685:Biological Factors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004719:Endomyocardial Fibrosis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D001685:Biological Factors; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta