Role of NOD1 in heart failure progression via regulation of Ca2+ handling

Instituto de Salud Carlos III; CP11/00080Instituto de Salud Carlos III; PI14/01078Ministerio de Economía y competitividad; SAF2014-52492RMinisterio de Economía y competitividad; SAF2014-57190RMinisterio de Economía y competitividad; RTC2015-374

Role of NOD1 in heart failure progression via regulation of Ca2+ handling

[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 dynamic impairment linked to HF, including smaller and longer intracellular Ca concentration transients and a lesser sarcoplasmic reticulum Ca load due to a down-regulation of the sarcoplasmic reticulum Ca-adenosine triphosphatase pump and by augmented levels of the Na/Ca exchanger. Increased diastolic Ca 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 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 release and with a prevention of the hyperphosphorylation of ryanodine receptors under isoproterenol administration in Nod1-PMI mice. [Conclusions]: NOD1 modulated intracellular Ca mishandling in HF, emerging as a new target for HF therapy.This work was supported by grants CP11/00080 and PI14/01078 from Instituto de Salud Carlos III (ISCIII); SAF2014-52492-R, SAF2014-57190-R, and RTC2015-3741 from Ministerio de Economía y Competitividad; Fondos Fondo Europeo de Desarrollo Regional; and Red de Investigación Cardiovascular (RIC) RD12/0042/0019. RIC is a network funded by the Carlos III Health Institute. Dr. Fernández Velasco is Miguel Servet researcher of ISCIII.Peer Reviewe

Role of NOD1 in Heart Failure Progression via Regulation of Ca2+ Handling.

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.post-prin