title: Role of NOD1 in Heart Failure Progression via Regulation of Ca2+Handling.
abstract: BACKGROUND
  Heart failure (HF) is a complex syndrome associated with a maladaptive innate immune system response that leads to deleterious cardiac remodeling. However, the underlying mechanisms of this syndrome are poorly understood. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a newly recognized innate immune sensor involved in cardiovascular diseases.
  
  
  OBJECTIVE
  This study evaluated the role of NOD1 in HF progression.
  
  
  METHODS
  NOD1 was examined in human failing myocardium and in a post-myocardial infarction (PMI) HF model evaluated in wild-type (wt-PMI) and Nod1-/-mice (Nod1-/--PMI).
  
  
  RESULTS
  The NOD1 pathway was up-regulated in human and murine failing myocardia. Compared with wt-PMI, hearts from Nod1-/--PMI mice had better cardiac function and attenuated structural remodeling. Ameliorated cardiac function in Nod1-/--PMI mice was associated with prevention of Ca2+dynamic impairment linked to HF, including smaller and longer intracellular Ca2+concentration transients and a lesser sarcoplasmic reticulum Ca2+load due to a down-regulation of the sarcoplasmic reticulum Ca2+-adenosine triphosphatase pump and by augmented levels of the Na+/Ca2+exchanger. Increased diastolic Ca2+release in wt-PMI cardiomyocytes was related to hyperphosphorylation of ryanodine receptors, which was blunted in Nod1-/--PMI cardiomyocytes. Pharmacological blockade of NOD1 also prevented Ca2+mishandling in wt-PMI mice. Nod1-/--PMI mice showed significantly fewer ventricular arrhythmias and lower mortality after isoproterenol administration. These effects were associated with lower aberrant systolic Ca2+release and with a prevention of the hyperphosphorylation of ryanodine receptors under isoproterenol administration in Nod1-/--PMI mice.
  
  
  CONCLUSIONS
  NOD1 modulated intracellular Ca2+mishandling in HF, emerging as a new target for HF therapy.
authors.affiliation: Innate Immune Response Group, Instituto de Investigación La Paz, La Paz University Hospital, Madrid, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Val-Blasco
authors.affiliation: Department of Cardiology, University Hospital Ramón y Cajal/University Francisco de Vitoria, Madrid, Spain.
authors.forename: María Jose G M
authors.initials: MJGM
authors.lastname: Piedras
authors.affiliation: Unidad de Hipertensión, Instituto de Investigación i+12 Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Ruiz-Hurtado
authors.affiliation: Cardiology Department, Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, Servicio Gallego de Salud, Universidade da Coruña, Coruña, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Suarez
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Prieto
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gonzalez-Ramos
authors.affiliation: Departament of Pharmacology, School of Medicine, Complutense University, Madrid, Spain.
authors.forename: Nieves
authors.initials: N
authors.lastname: Gómez-Hurtado
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain; Departament of Pharmacology, School of Medicine, Complutense University, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Delgado
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, California.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Pereira
authors.affiliation: Innate Immune Response Group, Instituto de Investigación La Paz, La Paz University Hospital, Madrid, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Benito
authors.affiliation: Department of Cardiology, University Hospital Ramón y Cajal/University Francisco de Vitoria, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Zaragoza
authors.affiliation: Biobanco A Coruña, Complexo Hospitalario Universitario A Coruña e Instituto de Investigación Biomédica, Coruña, Spain.
authors.forename: Nieves
authors.initials: N
authors.lastname: Domenech
authors.affiliation: Cardiology Department, Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, Servicio Gallego de Salud, Universidade da Coruña, Coruña, Spain.
authors.forename: María Generosa
authors.initials: MG
authors.lastname: Crespo-Leiro
authors.affiliation: Cardiology Department, Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, Servicio Gallego de Salud, Universidade da Coruña, Coruña, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vasquez-Echeverri
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nuñez
authors.affiliation: Innate Immune Response Group, Instituto de Investigación La Paz, La Paz University Hospital, Madrid, Spain; Center for Biomedical Research Network, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Madrid, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Lopez-Collazo
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain. Electronic address: lbosca@iib.uam.es.
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.affiliation: Innate Immune Response Group, Instituto de Investigación La Paz, La Paz University Hospital, Madrid, Spain. Electronic address: mvelasco@iib.uam.es.
authors.forename: María
authors.initials: M
authors.lastname: Fernández-Velasco
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D018450:Disease Progression; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium
keywords: calcium; cardiac arrhythmia; cardiac dysfunction; innate immune system; myocardial infarction; ryanodine receptor