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J Am Coll Cardiol. 2017 Jan 31;69(4):423-433. doi: 10.1016/j.jacc.2016.10.073.

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

Author information

1
Innate Immune Response Group, Instituto de Investigación La Paz, La Paz University Hospital, Madrid, Spain.
2
Department of Cardiology, University Hospital Ramón y Cajal/University Francisco de Vitoria, Madrid, Spain.
3
Unidad de Hipertensión, Instituto de Investigación i+12 Hospital Universitario 12 de Octubre, Madrid, Spain.
4
Cardiology Department, Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, Servicio Gallego de Salud, Universidade da Coruña, Coruña, Spain.
5
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
6
Departament of Pharmacology, School of Medicine, Complutense University, Madrid, Spain.
7
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain; Departament of Pharmacology, School of Medicine, Complutense University, Madrid, Spain.
8
Department of Pharmacology, University of California, Davis, Davis, California.
9
Biobanco A Coruña, Complexo Hospitalario Universitario A Coruña e Instituto de Investigación Biomédica, Coruña, Spain.
10
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan.
11
Innate Immune Response Group, Instituto de Investigación La Paz, La Paz University Hospital, Madrid, Spain; Center for Biomedical Research Network, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Madrid, Spain.
12
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid, Spain. Electronic address: lbosca@iib.uam.es.
13
Innate Immune Response Group, Instituto de Investigación La Paz, La Paz University Hospital, Madrid, Spain. Electronic address: mvelasco@iib.uam.es.

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

PMID:
28126160
DOI:
10.1016/j.jacc.2016.10.073
[Indexed for MEDLINE]
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