title: NOD1, a new player in cardiac function and calcium handling.
abstract: OBJECTIVE
  Inflammation is a significant contributor to cardiovascular disease and its complications; however, whether the myocardial inflammatory response is harmonized after cardiac injury remains to be determined. Some receptors of the innate immune system, including the nucleotide-binding oligomerization domain-like receptors (NLRs), play key roles in the host response after cardiac damage. Nucleotide-binding oligomerization domain containing 1 (NOD1), a member of the NLR family, is expressed in the heart, but its functional role has not been elucidated. We determine whether selective NOD1 activation modulates cardiac function and Ca(2+) signalling.
  
  
  RESULTS
  Mice were treated for 3 days with the selective NOD1 agonist C12-iE-DAP (iE-DAP), and cardiac function and Ca(2+) cycling were assessed. We found that iE-DAP treatment resulted in cardiac dysfunction, measured as a decrease in ejection fraction and fractional shortening. Cardiomyocytes isolated from iE-DAP-treated mice displayed a decrease in the L-type Ca(2+) current, [Ca(2+)]i transients and Ca(2+) load, and decreased expression of phospho-phospholamban, sarcoplasmic reticulum-ATPase, and Na(+)-Ca(2+) exchanger. Furthermore, iE-DAP prompted 'diastolic Ca(2+) leak' in cardiomyocytes, resulting from increased Ca(2+) spark frequency and RyR2 over-phosphorylation. Importantly, these iE-DAP-induced changes in Ca(2+) cycling were lost in NOD1(-/-) mice, indicating that iE-DAP exerts its actions through NOD1. Co-treatment of mice with iE-DAP and a selective inhibitor of NF-κB (BAY11-7082) prevented cardiac dysfunction and Ca(2+) handling impairment induced by iE-DAP.
  
  
  CONCLUSIONS
  Our data provide the first evidence that NOD1 activation induces cardiac dysfunction associated with excitation-contraction coupling impairment through NF-κB activation and uncover a new pro-inflammatory player in the regulation of cardiovascular function.
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Delgado
authors.affiliation: Instituto de Investigación i + 12 Hospital Universitario 12 de Octubre and Instituto Pluridisciplinar, UCM, Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Ruiz-Hurtado
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, 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.
authors.forename: Silvia
authors.initials: S
authors.lastname: González-Ramos
authors.affiliation: Departamento de Bioquímica, Cinvestav-IPN, México.
authors.forename: Angelica
authors.initials: A
authors.lastname: Rueda
authors.affiliation: Instituto de Investigación Hospital Universitario La PAZ, IDIPAZ, Madrid, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Benito
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: 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: Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria e Instituto Universitario de Investigación en Neuroquímica, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain.
authors.forename: Esmerilda G
authors.initials: EG
authors.lastname: Delicado
authors.affiliation: Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria e Instituto Universitario de Investigación en Neuroquímica, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Pérez-Sen
authors.affiliation: Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria e Instituto Universitario de Investigación en Neuroquímica, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Miras-Portugal
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain mvelasco@iib.uam.es maria.fernandez@idipaz.es lbosca@iib.uam.es.
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.affiliation: Instituto de Investigación Hospital Universitario La PAZ, IDIPAZ, Madrid, Spain mvelasco@iib.uam.es maria.fernandez@idipaz.es lbosca@iib.uam.es.
authors.forename: Maria
authors.initials: M
authors.lastname: Fernández-Velasco
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D056966:Excitation Contraction Coupling / Q000187:drug effects; D018836:Inflammation Mediators / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013318:Stroke Volume; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left / Q000187:drug effects; D000099211:Phospholamban
chemical_list: D000893:Anti-Inflammatory Agents; D002118:Calcium; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban; C507873:Nod1 protein, mouse
keywords: Ca2+ handling; Ca2+ sparks; Cardiac dysfunction; Innate immune system; NF-κB; NOD1