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 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.

Keywords: calcium; cardiac arrhythmia; cardiac dysfunction; innate immune system; myocardial infarction; ryanodine receptor.