Abstract
BackgroundHeart 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. ObjectivesThis study evaluated the role of NOD1 in HF progression. MethodsNOD1 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). ResultsThe 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. ConclusionsNOD1 modulated intracellular Ca2+ mishandling in HF, emerging as a new target for HF therapy.
Highlights
Heart failure (HF) is a complex syndrome associated with a maladaptive innate immune system response that leads to deleterious cardiac remodeling
Immunohistochemical analysis of myocardial tissue obtained from HF patients and unused healthy myocardia from transplant donors demonstrated higher levels of Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in HF than in healthy heart samples, which were localized to the rod-shaped cardiomyocyte population (Figure 1A; immunostaining control specimens are presented in Online Figure 1)
We examined NOD1 protein levels in cardiac tissue from mice with HF induced by myocardial infarction (MI)
Summary
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). 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 downregulation of the sarcoplasmic reticulum Ca2+-adenosine triphosphatase pump and by augmented levels of the Na+/Ca2+ exchanger. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
