Almudena Val-Blasco, María Jose G.M. Piedras, Gema Ruiz-Hurtado, Natalia Suarez, Patricia Prieto, Silvia Gonzalez-Ramos, Nieves Gómez-Hurtado, Carmen Delgado, Laetitia Pereira, Gemma Benito, Carlos Zaragoza, Nieves Domenech, María Generosa Crespo-Leiro, Daniel Vasquez-Echeverri, Gabriel Nuñez, Eduardo Lopez-Collazo, Lisardo Boscá, María Fernández-Velasco

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. This study evaluated the role of NOD1 in HF progression. 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). 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 Ca(2+) dynamic impairment linked to HF, including smaller and longer intracellular Ca(2+) concentration transients and a lesser sarcoplasmic reticulum Ca(2+) load due to a down-regulation of the sarcoplasmic reticulum Ca(2+)-adenosine triphosphatase pump and by augmented levels of the Na(+)/Ca(2+) exchanger. Increased diastolic Ca(2+) 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 Ca(2+) 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 Ca(2+) release and with a prevention of the hyperphosphorylation of ryanodine receptors under isoproterenol administration in Nod1(-/-)-PMI mice. NOD1 modulated intracellular Ca(2+) mishandling in HF, emerging as a new target for HF therapy.