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 prote...

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Published in:Journal of the American College of Cardiology 2017-01, Vol.69 (4), p.423-433
Main Authors: Val-Blasco, Almudena, BsC, Piedras, María Jose G.M., PhD, Ruiz-Hurtado, Gema, PhD, Suarez, Natalia, PhD, Prieto, Patricia, PhD, Gonzalez-Ramos, Silvia, BsC, Gómez-Hurtado, Nieves, PhD, Delgado, Carmen, PhD, Pereira, Laetitia, PhD, Benito, Gemma, BsC, Zaragoza, Carlos, PhD, Domenech, Nieves, PhD, Crespo-Leiro, María Generosa, MD, PhD, Vasquez-Echeverri, Daniel, PhD, Nuñez, Gabriel, MD, PhD, Lopez-Collazo, Eduardo, PhD, Boscá, Lisardo, PhD, Fernández-Velasco, María, PhD
Format: Article
Language:English
Subjects:
calcium
cardiac arrhythmia
cardiac dysfunction
Cardiology
Cardiomyocytes
Cardiovascular
Gangrene
Heart attacks
Heart failure
Immune system
innate immune system
Internal Medicine
Medical prognosis
myocardial infarction
Proteins
Rodents
ryanodine receptor
Tumor necrosis factor-TNF
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Summary: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.
ISSN:0735-1097
1558-3597
DOI:10.1016/j.jacc.2016.10.073