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. 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 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. Conclusions NOD1 modulated intracellular Ca 2+ mishandling in HF, emerging as a new target for HF therapy.