Role of NOD1 in Heart Failure Progression via Regulation of Ca 2+ Handling

Val‐Blasco, Almudena; Piedras, Maria J.; Ruiz‐Hurtado, Gema; Suárez, Natalia; Prieto, Patricia; González-Ramos, Silvia; Gómez-Hurtado, Nieves; Delgado, Carmen; Pereira, Laëtitia; Benito, Gemma; Zaragoza, Carlos; Doménech, Nieves; Crespo-Leiro, María G.; Vásquez-Echeverri, Daniel; Núñez, Gabriel; López‐Collazo, Eduardo; Boscá, Lisardo; Fernández‐Velasco, María

doi:10.1016/j.jacc.2016.10.073

Cited by 28 publications

(41 citation statements)

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“…So far, only a limited number of studies in vivo have shown the effect of NOD1 in the cardiovascular field (23)(24)(25)(26). Consistent with a previous report (27), we here establish that Nod1 deficiency prevents early atherosclerosis development in Apoe 2/2 mice.…”

Section: Discussionsupporting

confidence: 92%

Endothelial NOD1 directs myeloid cell recruitment in atherosclerosis through VCAM‐1

et al. 2018

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Atherosclerosis is a chronic disease characterized by vascular lipid retention and inflammation, and pattern recognition receptors (PRRs) are important contributors in early stages of the disease. Given the implication of the intracellular PRR nucleotide‐binding oligomerization domain 1 (NOD1) in cardiovascular diseases, we investigated its contribution to early atherosclerosis. We evidenced NOD1 induction in atherosclerotic human and mouse tissues, predominantly in vascular endothelial cells. Accordingly, NOD1 genetic inactivation in Apoe−/− mice reduced not only atherosclerosis burden, but also monocyte and neutrophil accumulation in atheromata. Of note, in the presence of either peptidoglycan or oxidized LDLs, endothelial NOD1 triggered VCAM‐1 up‐regulation through the RIP2‐NF‐κB axis in an autocrine manner, enhancing firm adhesion of both sets of myeloid cells to the inflamed micro‐ and macro vasculature in vivo. Our data define a major proatherogenic role for endothelial NOD1 in early leukocyte recruitment to the athero‐prone vasculature, thus introducing NOD1 as an innovative therapeutic target and potential prognostic molecule.—González‐Ramos, S., Paz‐García, M., Rius, C., del Monte‐Monge, A., Rodríguez, C., Fernández‐García, V., Andrés, V., Martínez‐González, J., Lasunción, M. A., Martín‐Sanz, P., Soehnlein, O., Boscá, L. Endothelial NOD1 directs myeloid cell recruitment in atherosclerosis through VCAM‐1. FASEB J. 33, 3912–3921 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 92%

Endothelial NOD1 directs myeloid cell recruitment in atherosclerosis through VCAM‐1

et al. 2018

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“…Although interest in the study of NOD1 in cardiovascular diseases has increased lately, [ 12 , 13 , 14 , 15 ] its role in destabilizing atherosclerotic plaque is still lacking. In this study, our aim is to investigate the contribution of NOD1 to key characteristics of plaque vulnerability.…”

Section: Introductionmentioning

confidence: 99%

Deletion or Inhibition of NOD1 Favors Plaque Stability and Attenuates Atherothrombosis in Advanced Atherogenesis

González-Ramos

Fernández-García

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et al. 2020

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Atherothrombosis, the main cause of acute coronary syndromes (ACS), is characterized by the rupture of the atherosclerotic plaque followed by the formation of thrombi. Fatal plaque rupture sites show large necrotic cores combined with high levels of inflammation and thin layers of collagen. Plaque necrosis due to the death of macrophages and smooth muscle cells (SMCs) remains critical in the process. To determine the contribution of the innate immunity receptor NOD1 to the stability of atherosclerotic plaque, Apoe−/− and Apoe−/− Nod1−/− atherosclerosis prone mice were placed on a high-fat diet for 16 weeks to assess post-mortem advanced atherosclerosis in the aortic sinus. The proliferation and apoptosis activity were analyzed, as well as the foam cell formation capacity in these lesions and in primary cultures of macrophages and vascular SMCs obtained from both groups of mice. Our results reinforce the preeminent role for NOD1 in human atherosclerosis. Advanced plaque analysis in the Apoe−/− atherosclerosis model suggests that NOD1 deficiency may decrease the risk of atherothrombosis by decreasing leukocyte infiltration and reducing macrophage apoptosis. Furthermore, Nod1−/− SMCs exhibit higher proliferation rates and decreased apoptotic activity, contributing to thicker fibrous caps with reduced content of pro-thrombotic collagen. These findings demonstrate a direct link between NOD1 and plaque vulnerability through effects on both macrophages and SMCs, suggesting promising insights for early detection of biomarkers for treating patients before ACS occurs.

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“…Whether the myocardial inflammatory response impairs cardiac damage is a question of broad significance. Recent studies indicate that some receptors of the innate immune system, including nucleotide-binding oligomerization domain-like receptors (NLRs), play significant roles in the host response after cardiac damage ( Bullón et al, 2016 ; Monnerat et al, 2016 ; Val-Blasco et al, 2017a ). Nucleotide-binding oligomerization domain (NOD) receptors are NLR family members that recognize conserved motifs of bacterial peptidoglycans in many Gram-negative bacteria ( Caruso et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have demonstrated a role for NOD1 in the progression of cardiovascular diseases, including atherosclerosis and diabetic cardiomyopathy ( Prieto et al, 2014 ; Kanno et al, 2015 ; Val-Blasco et al, 2017b ). We have recently shown that NOD1 is upregulated in both mouse and human failing myocardium, and its genetic deletion or pharmacological blockade prevents cardiac dysfunction and deleterious remodeling in failing hearts principally by preventing the HF-related Ca 2+ mishandling ( Val-Blasco et al, 2017a ). Conversely, activation of NOD1 promotes a dysregulation of the intracellular Ca 2+ dynamics, similar to those observed in HF ( Delgado et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

“…Depressed systolic Ca 2+ release, the decline in the SR-Ca 2+ load, and the increased Ca 2+ diastolic leak seem to be key players in HF progression, and these changes worsen under chronic β-adrenergic activation. We recently showed that NOD1 modulates intracellular Ca 2+ handling in human and experimental failing hearts ( Val-Blasco et al, 2017a ); however, the role of NOD1 in the modulation of Ca 2+ handling under β-adrenergic stimulation has not been investigated. Using a mouse HF model, we determined whether the deficiency of NOD1 impairs the modulation of Ca 2+ dynamics under β-adrenergic stimulation.…”

Section: Introductionmentioning

confidence: 99%

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Deficiency of NOD1 Improves the β-Adrenergic Modulation of Ca2+ Handling in a Mouse Model of Heart Failure

et al. 2018

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Heart failure (HF) is a complex syndrome characterized by cardiac dysfunction, Ca2+ mishandling, and chronic activation of the innate immune system. Reduced cardiac output in HF leads to compensatory mechanisms via activation of the adrenergic nervous system. In turn, chronic adrenergic overstimulation induces pro-arrhythmic events, increasing the rate of sudden death in failing patients. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an innate immune modulator that plays a key role in HF progression. NOD1 deficiency in mice prevents Ca2+ mishandling in HF under basal conditions, but its role during β-adrenergic stimulation remains unknown. Here, we evaluated whether NOD1 regulates the β-adrenergic modulation of Ca2+ signaling in HF. Ca2+ dynamics were examined before and after isoproterenol perfusion in cardiomyocytes isolated from healthy and from post-myocardial infarction (PMI) wild-type (WT) and Nod1-/- mice. Isoproterenol administration induced similar effects on intracellular [Ca2+]i transients, cell contraction, and sarcoplasmic reticulum (SR)-Ca2+ load in healthy WT and Nod1-/- cells. However, compared with WT-PMI cells, isoproterenol exposure induced a significant increase in the [Ca2+]i transients and cell contraction parameters in Nod1-/--PMI cells, which mainly due to an increase in SR-Ca2+ load. NOD1 deficiency also prevented the increase in diastolic Ca2+ leak (Ca2+ waves) induced by isoproterenol in PMI cells. mRNA levels of β1 and β2 adrenergic receptors were significantly higher in Nod1-/--PMI hearts vs WT-PMI hearts. Healthy cardiomyocytes pre-treated with the selective agonist of NOD1, iE-DAP, and perfused with isoproterenol showed diminished [Ca2+]i transients amplitude, cell contraction, and SR-Ca2+ load compared with vehicle-treated cells. iE-DAP-treated cells also presented increased diastolic Ca2+ leak under β-adrenergic stimulation. The selectivity of iE-DAP on Ca2+ handling was validated by pre-treatment with the inactive analog of NOD1, iE-Lys. Overall, our data establish that NOD1 deficiency improves the β-adrenergic modulation of Ca2+ handling in failing hearts.

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Role of NOD1 in Heart Failure Progression via Regulation of Ca 2+ Handling

Cited by 28 publications

References 18 publications

Endothelial NOD1 directs myeloid cell recruitment in atherosclerosis through VCAM‐1

Endothelial NOD1 directs myeloid cell recruitment in atherosclerosis through VCAM‐1

Deletion or Inhibition of NOD1 Favors Plaque Stability and Attenuates Atherothrombosis in Advanced Atherogenesis

Deficiency of NOD1 Improves the β-Adrenergic Modulation of Ca2+ Handling in a Mouse Model of Heart Failure

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