Val-Blasco, A.Garcia Miguel Piedras, María JoséRuiz-Hurtado, G.Suárez, N.Prieto, P.González Ramos, S.Gómez Hurtado, N.Delgado, C.Pereira, L.Benito, G.Zaragoza Sánchez, CarlosDomenech, N.Crespo Leiro, M.Vasquez Echeverri, D.Núñez, G.López Collazo, E.Boscá, L.Fernández Velasco, M.2019-11-162019-11-1620170735-1097http://hdl.handle.net/10641/1737BACKGROUND: 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. OBJECTIVES: 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.engAtribución-NoComercial-SinDerivadas 3.0 Españahttp://creativecommons.org/licenses/by-nc-nd/3.0/es/CalciumCardiac arrhythmiaCardiac dysfunctionInnate immune systemMyocardial infarctionRyanodine receptorjournal articleopen access10.1016/j.jacc.2016.10.073