title: NOD1 receptor is up-regulated in diabetic human and murine myocardium.
abstract: Type 2 diabetes has a complex pathology that involves a chronic inflammatory state. Emerging evidence suggests a link between the innate immune system receptor NOD1 (nucleotide-binding and oligomerization domain 1) and the pathogenesis of diabetes, in monocytes and hepatic and adipose tissues. The aim of the present study was to assess the role of NOD1 in the progression of diabetic cardiomyopathy. We have measured NOD1 protein in cardiac tissue from Type 2 diabetic (db) mice. Heart and isolated cardiomyocytes from db mice revealed a significant increase in NOD1, together with an up-regulation of nuclear factor κB (NF-κB) and increased apoptosis. Heart tissue also exhibited an enhanced expression of pro-inflammatory cytokines. Selective NOD1 activation with C12-γ-D-glutamyl-m-diaminopimelic acid (iEDAP) resulted in an increased NF-κB activation and apoptosis, demonstrating the involvement of NOD1 both in wild-type and db mice. Moreover, HL-1 cardiomyocytes exposed to elevated concentrations of glucose plus palmitate displayed an enhanced NF-κB activity and apoptotic profile, which was prevented by silencing of NOD1 expression. To address this issue in human pathology, NOD1 expression was evaluated in myocardium obtained from patients with Type 2 diabetes (T2DMH) and from normoglycaemic individuals without cardiovascular histories (NH). We have found that NOD1 was expressed in both NH and T2DMH; however, NOD1 expression was significantly pronounced in T2DMH. Furthermore, both the pro-inflammatory cytokine tumour necrosis factor α (TNF-α) and the apoptosis mediator caspase-3 were up-regulated in T2DMH samples. Taken together, our results define an active role for NOD1 in the heightened inflammatory environment associated with both experimental and human diabetic cardiac disease.
authors.affiliation: *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Prieto
authors.affiliation: †Instituto de Investigación Hospital Universitario La Paz (IDIPAZ), Madrid, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Vallejo-Cremades
authors.affiliation: †Instituto de Investigación Hospital Universitario La Paz (IDIPAZ), Madrid, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Benito
authors.affiliation: ‡Departamento de Anatomía Patológica, Hospital Universitario La Paz, Universidad Autonoma de Madrid, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: González-Peramato
authors.affiliation: *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Francés
authors.affiliation: *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Agra
authors.affiliation: *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Terrón
authors.affiliation: *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gónzalez-Ramos
authors.affiliation: §Centro de Investigaciones Biológicas. Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Delgado
authors.affiliation: ¶Universidad CEU San Pablo, Madrid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Ruiz-Gayo
authors.affiliation: **Hospital Militar de Managua, Managua, Nicaragua.
authors.forename: Ivette
authors.initials: I
authors.lastname: Pacheco
authors.affiliation: ††Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Velasco-Martín
authors.affiliation: ††Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Regadera
authors.affiliation: *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
authors.affiliation: †Instituto de Investigación Hospital Universitario La Paz (IDIPAZ), Madrid, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Collazo
authors.affiliation: *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain.
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.affiliation: †Instituto de Investigación Hospital Universitario La Paz (IDIPAZ), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Fernández-Velasco
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism*; D010168:Palmitates / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; D010168:Palmitates; D005947:Glucose