Roles of PAD4 and NETosis in Experimental Atherosclerosis and Arterial Injury

Franck, G; Mawson, Thomas L.; Folco, Eduardo J.; Molinaro, Roberto; Ruvkun, Victoria; Engelbertsen, Daniel; Liu, Xin; Tesmenitsky, Yevgenia; Shvartz, Eugenia; Sukhova, Galina K.; Michel, Jean-Baptiste; Nicoletti, Antonino; Lichtman, Andrew H.; Wagner, Denisa D.; Croce, Kevin; Libby, Peter

doi:10.1161/circresaha.117.312494

Cited by 221 publications

(161 citation statements)

References 33 publications

(34 reference statements)

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“…Interestingly, a recent study showed that PAD4 deficiency in hematopoietic cells did not modulate atherosclerotic plaque burden, which is different from our study ( 43 ). The discrepancies may be due to the differences in atherosclerotic murine model and the gender.…”

Section: Discussioncontrasting

confidence: 99%

Myeloid-Specific Deletion of Peptidylarginine Deiminase 4 Mitigates Atherosclerosis

et al. 2018

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Increasing evidence suggests that neutrophil extracellular traps (NETs) may play a role in promoting atherosclerotic plaque lesions in humans and in murine models. The exact pathways involved in NET-driven atherogenesis remain to be systematically characterized. To assess the extent to which myeloid-specific peptidylarginine deiminase 4 (PAD4) and PAD4-dependent NET formation contribute to atherosclerosis, mice with myeloid-specific deletion of PAD4 were generated and backcrossed to Apoe−/− mice. The kinetics of atherosclerosis development were determined. NETs, but not macrophage extracellular traps, were present in atherosclerotic lesions as early as 3 weeks after initiating high-fat chow. The presence of NETs was associated with the development of atherosclerosis and with inflammatory responses in the aorta. Specific deletion of PAD4 in the myeloid lineage significantly reduced atherosclerosis burden in association with diminished NET formation and reduced inflammatory responses in the aorta. NETs stimulated macrophages to synthesize inflammatory mediators, including IL-1β, CCL2, CXCL1, and CXCL2. Our data support the notion that NETs promote atherosclerosis and that the use of specific PAD4 inhibitors may have therapeutic benefits in this potentially devastating condition.

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Section: Discussioncontrasting

confidence: 99%

Myeloid-Specific Deletion of Peptidylarginine Deiminase 4 Mitigates Atherosclerosis

et al. 2018

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“…Finally, it would be of interest to further classify cause of death to better understand potential clinical implications of dsDNA as a biomarker. Nor could we assess underlying STEMI aetiologies, such as plaque erosion versus rupture, in which NETs might play differential roles 40,41 .…”

Section: Discussionmentioning

confidence: 99%

Double-Stranded DNA and NETs Components in Relation to Clinical Outcome After ST-Elevation Myocardial Infarction

Langseth

Helseth

Ritschel

et al. 2020

Sci Rep

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Neutrophil extracellular traps (NETs) have been implicated in atherothrombosis; however, their potential role as markers of risk is unclear. We investigated whether circulating NETs-related components associated with clinical outcome and hypercoagulability in St-elevation myocardial infarction (STEMI). In this observational cohort study, STEMI patients admitted for PCI (n = 956) were followed for median 4.6 years, recording 190 events (reinfarction, unscheduled revascularization, stroke, heart failure hospitalization, or death). Serum drawn median 18 hours post-PCI was used to quantify double-stranded DNA (dsDNA) and the more specific NETs markers myeloperoxidase-DNA and citrullinated histone 3. Levels of the NETs markers did not differ significantly between groups with/without a primary composite endpoint. However, patients who died (n = 76) had higher dsDNA compared to survivors (p < 0.001). Above-median dsDNA was associated with an increased number of deaths (54 vs. 22, p < 0.001). dsDNA in the upper quartiles (Q) was associated with increased mortality (Q3 vs. Q1 + 2 adjusted HR: 1.89 [95% CI 1.03 to 3.49], p = 0.041 and Q4 vs. Q1 + 2 adjusted HR: 2.28 [95% CI 1.19 to 4.36], p = 0.013). dsDNA was weakly correlated with D-dimer (r s = 0.17, p < 0.001). dsDNA levels associated with increased all-cause mortality, yet weakly with hypercoagulability in STEMI patients. The prognostic significance of potentially NETs-related markers requires further exploration. Acute coronary syndrome (ACS) often results from erosion or rupture of atherosclerotic plaques followed by thrombosis, ischemia, and myocardial injury. It has been suggested that the risk-stratification of ACS patients should be expanded to include new soluble biomarkers, which may help individualize treatment 1. Potential candidates include components of the innate immune response, widely accepted to be important in the immediate aftermath of ACS, yet still not completely understood. Neutrophil extracellular traps (NETs) were first described in 2004 by Brinkmann and colleagues, who documented the expulsion of extracellular webbed structures comprising deoxyribonucleic acid (DNA) and histones, studded with neutrophil granule proteins 2. The process of NETs release, or NETosis, is initiated by granular proteins such as myeloperoxidase (MPO), neutrophil elastase, and peptidylarginine deiminase 4 3. The latter mediates the citrullination of histone 3, inducing chromatin decondensation before extracellular release 3. Circulating NETs-associated components may contribute to endothelial dysfunction and plaque instability 4 , as well as coronary thrombus formation 5 by activating platelets, triggering the coagulation cascade, and trapping thrombus constituents 6,7. Nevertheless, it is not yet clear how NETs per se are implicated in the fine balance between beneficial and deleterious effects of inflammation after revascularization.

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“…Of note, several studies suggest an imbalance between NETosis and NET degradation in autoimmune diseases, which may in part account for the increased CVD risk in these patients (Carmona-Rivera et al, 2015;Kessenbrock et al, 2009;Khandpur et al, 2013). While a recent study shows inhibiting NETosis via Pad4 deficiency in Ldlr −/− mice does not impede atherogenesis but prevents EC injury and thrombus formation (Franck et al, 2018), applying myeloid-specific Pad4-deficient Figure 3. The effect of type-I IFNs during atherosclerosis development in different models.…”

Section: Neutrophilsmentioning

confidence: 99%

Type-I interferons in atherosclerosis

Chen

Tas

Winther

2019

Journal of Experimental Medicine

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The contribution of dyslipidemia and inflammation in atherosclerosis is well established. Along with effective lipid-lowering treatments, the recent success of clinical trials with anti-inflammatory therapies and the accelerated atherosclerosis in many autoimmune diseases suggest that targeting inflammation may open new avenues for the prevention and the treatment for cardiovascular diseases (CVDs). In the past decades, studies have widened the role of type-I interferons (IFNs) in disease, from antivirus defense to autoimmune responses and immuno-metabolic syndromes. While elevated type-I IFN level in serum is associated with CVD incidence in patients with interferonopathies, experimental data have attested that type-I IFNs affect plaque-residing macrophages, potentiate foam cell and extracellular trap formation, induce endothelial dysfunction, alter the phenotypes of dendritic cells and T and B lymphocytes, and lead to exacerbated atherosclerosis outcomes. In this review, we discuss the production and the effects of type-I IFNs in different atherosclerosis-associated cell types from molecular biology studies, animal models, and clinical observations, and the potential of new therapies against type-I IFN signaling for atherosclerosis.

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Roles of PAD4 and NETosis in Experimental Atherosclerosis and Arterial Injury

Abstract: These results indicate that PAD4 from bone marrow-derived cells and NETs do not influence chronic experimental atherogenesis, but participate causally in acute thrombotic complications of intimal lesions that recapitulate features of superficial erosion.

Cited by 221 publications

References 33 publications

Myeloid-Specific Deletion of Peptidylarginine Deiminase 4 Mitigates Atherosclerosis

Myeloid-Specific Deletion of Peptidylarginine Deiminase 4 Mitigates Atherosclerosis

Double-Stranded DNA and NETs Components in Relation to Clinical Outcome After ST-Elevation Myocardial Infarction

Type-I interferons in atherosclerosis

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