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1.
Nature ; 634(8033): 447-456, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39232165

RESUMEN

Systemic immune responses caused by chronic hypercholesterolaemia contribute to atherosclerosis initiation, progression and complications1. However, individuals often change their dietary habits over time2, and the effects of an alternating high-fat diet (HFD) on atherosclerosis remain unclear. Here, to address this relevant issue, we developed a protocol using atherosclerosis-prone mice to compare an alternating versus continuous HFD while maintaining similar overall exposure periods. We found that an alternating HFD accelerated atherosclerosis in Ldlr-/- and Apoe-/- mice compared with a continuous HFD. This pro-atherogenic effect of the alternating HFD was also observed in Apoe-/-Rag2-/- mice lacking T, B and natural killer T cells, ruling out the role of the adaptive immune system in the observed phenotype. Discontinuing the HFD in the alternating HFD group downregulated RUNX13, promoting inflammatory signalling in bone marrow myeloid progenitors. After re-exposure to an HFD, these cells produced IL-1ß, leading to emergency myelopoiesis and increased neutrophil levels in blood. Neutrophils infiltrated plaques and released neutrophil extracellular traps, exacerbating atherosclerosis. Specific depletion of neutrophils or inhibition of IL-1ß pathways abolished emergency myelopoiesis and reversed the pro-atherogenic effects of the alternating HFD. This study highlights the role of IL-1ß-dependent neutrophil progenitor reprogramming in accelerated atherosclerosis induced by alternating HFD.


Asunto(s)
Aterosclerosis , Reprogramación Celular , Dieta Alta en Grasa , Neutrófilos , Animales , Femenino , Masculino , Ratones , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Células de la Médula Ósea/citología , Dieta Alta en Grasa/efectos adversos , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Trampas Extracelulares , Inflamación/patología , Interleucina-1beta/metabolismo , Ratones Endogámicos C57BL , Mielopoyesis , Neutrófilos/metabolismo , Neutrófilos/patología , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Receptores de LDL/deficiencia , Receptores de LDL/genética , Transducción de Señal
2.
PLoS One ; 19(8): e0308273, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39088551

RESUMEN

BACKGROUND: Exposure to ionizing radiation has been linked to cardiovascular diseases. However, the impact of moderate doses of radiation on abdominal aortic aneurysm (AAA) remains unknown. METHODS: Angiotensin II-infused Apoe-/- mice were irradiated (acute, 1 Gray) either 3 days before (Day-3) or 1 day after (Day+1) pomp implantation. Isolated primary aortic vascular smooth muscle cells (VSMCs) were irradiated (acute 1 Gray) for mechanistic studies and functional testing in vitro. RESULTS: Day-3 and Day+1 irradiation resulted in a significant reduction in aorta dilation (Control: 1.39+/-0.12; Day-3: 1.12+/-0.11; Day+1: 1.15+/-0.08 mm, P<0.001) and AAA incidence (Control: 81.0%; Day-3: 33.3%, Day+1: 53.3%) compared to the non-irradiated group. Day-3 and Day+1 irradiation led to an increase in collagen content in the adventitia (Thickness control: 23.64+/-2.9; Day-3: 54.39+/-15.5; Day+1 37.55+/-10.8 mm, P = 0.006). However, the underlying protective mechanisms were different between Day-3 and Day+1 groups. Irradiation before Angiotensin II (AngII) infusion mainly modulated vascular smooth muscle cell (VSMC) phenotype with a decrease in contractile profile and enhanced proliferative and migratory activity. Irradiation after AngII infusion led to an increase in macrophage content with a local anti-inflammatory phenotype characterized by the upregulation of M2-like gene and IL-10 expression. CONCLUSION: Moderate doses of ionizing radiation mitigate AAA either through VSCM phenotype or inflammation modulation, depending on the time of irradiation.


Asunto(s)
Angiotensina II , Aneurisma de la Aorta Abdominal , Músculo Liso Vascular , Miocitos del Músculo Liso , Radiación Ionizante , Animales , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/etiología , Ratones , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efectos de la radiación , Músculo Liso Vascular/patología , Angiotensina II/farmacología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de la radiación , Miocitos del Músculo Liso/patología , Masculino , Modelos Animales de Enfermedad , Interleucina-10/metabolismo , Interleucina-10/genética , Colágeno/metabolismo , Proliferación Celular/efectos de la radiación
3.
Nat Commun ; 14(1): 4622, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37528097

RESUMEN

Caspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe-/- mice as well as hematopoietic deletion in Ldlr-/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe-/-Rag2-/-Card9-/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1ß production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.


Asunto(s)
Aterosclerosis , Humanos , Animales , Ratones , Aterosclerosis/metabolismo , Autofagia/genética , Apolipoproteínas E/genética , Lípidos , Proteínas Adaptadoras de Señalización CARD/metabolismo , Ratones Noqueados , Ratones Endogámicos C57BL
5.
Nat Commun ; 13(1): 6592, 2022 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-36329047

RESUMEN

JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk factor for dilation of both the ascending and descending thoracic aorta. Using single-cell RNA-seq, complementary genetically-modified mouse models, as well as pharmacological approaches, we found that JAK2V617F mutation was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages, and dissecting aneurysm through the recruitment of circulating monocytes at later stages. Finally, genetic manipulation of tissue-resident macrophages, or treatment with a Jak2 inhibitor, ruxolitinib, mitigated aortic wall inflammation and reduced aortic dilation and rupture. Overall, JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.


Asunto(s)
Aneurisma de la Aorta , Disección Aórtica , Ratones , Animales , Disección Aórtica/patología , Fenotipo , Mutación , Macrófagos/patología , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/complicaciones
6.
J Clin Invest ; 131(2)2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33258804

RESUMEN

The triggering receptor expressed on myeloid cells 1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our objective was to explore the role of TREM-1 in a mouse model of angiotensin II-induced (AngII-induced) AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalized with macrophages. Trem1 gene deletion (Apoe-/-Trem1-/-), as well as TREM-1 pharmacological blockade with LR-12 peptide, limited both AAA development and severity. Trem1 gene deletion attenuated the inflammatory response in the aorta, with a reduction of Il1b, Tnfa, Mmp2, and Mmp9 mRNA expression, and led to a decreased macrophage content due to a reduction of Ly6Chi classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6Chi monocyte aorta infiltration after AngII infusion through CD62L upregulation and promoted proinflammatory signature in the aorta, resulting in worsening AAA severity. AngII infusion stimulated TREM-1 expression and activation on Ly6Chi monocytes through AngII receptor type I (AT1R). In human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression. Finally, circulating levels of sTREM-1 were increased in patients with AAA when compared with patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in humans.


Asunto(s)
Angiotensina II/efectos adversos , Aneurisma de la Aorta Abdominal/metabolismo , Movimiento Celular/efectos de los fármacos , Monocitos/metabolismo , Receptor Activador Expresado en Células Mieloides 1/metabolismo , Angiotensina II/farmacología , Animales , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/patología , Movimiento Celular/genética , Eliminación de Gen , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Noqueados para ApoE , Monocitos/patología , Receptor Activador Expresado en Células Mieloides 1/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
7.
Angiogenesis ; 24(1): 47-55, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32989644

RESUMEN

Peripheral arterial disease occurs more frequently and has a worse prognosis in patients with chronic kidney disease (CKD). The receptor for advanced glycation end products (RAGE) is involved in multiple aspects of uremia-associated vasculopathy. Previous data suggest that the RAGE pathway may promote soluble fms-like tyrosine kinase 1 (sFlt1) production, an anti-angiogenic molecule. Thus, we tested the hypothesis that the deletion of AgeR would decrease sFlt1 production and improve post-ischemic revascularization in uremic condition. We used a well-established CKD model (5/6 nephrectomy) in WT and AgeR-/- C57/Bl6 mice. Hindlimb ischemia was induced by femoral artery ligation. Revascularization was evaluated by complementary approaches: ischemic limb retraction, LASCA imagery, and capillary density. The production of sFlt1 was assessed at both RNA and protein levels. After hindlimb ischemia, uremic mice showed slower functional recovery (p < 0.01), decreased reperfusion (p < 0.01), lower capillary density (p = 0.02), and increased circulating sFlt1 levels (p = 0.03). AgeR deletion restored post-ischemic angiogenesis and was protective from sFlt1 increase in uremic mice. These findings show the main role of RAGE in post-ischemic angiogenesis impairment associated with CKD. RAGE may represent a key target for building new therapeutic approaches to improve the outcome of CKD patients with PAD.


Asunto(s)
Eliminación de Gen , Isquemia/complicaciones , Neovascularización Fisiológica , Receptor para Productos Finales de Glicación Avanzada/deficiencia , Uremia/complicaciones , Receptor 1 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Animales , Biomarcadores/sangre , Línea Celular , Humanos , Ligandos , Masculino , Ratones Endogámicos C57BL , ARN/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Solubilidad , Regulación hacia Arriba
8.
J Transl Med ; 17(1): 261, 2019 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-31399109

RESUMEN

BACKGROUND: Cell therapy has been proposed for patients with critical limb ischemia (CLI). Autologous bone marrow derived cells (BMCs) have been mostly used, mesenchymal stem cells (MSCs) being an alternative. The aim of this study was to characterize two types of MSCs and evaluate their efficacy. METHODS: MSCs were obtained from CLI-patients BMCs. Stimulated- (S-) MSCs were cultured in endothelial growth medium. Cells were characterized by the expression of cell surface markers, the relative expression of 6 genes, the secretion of 10 cytokines and the ability to form vessel-like structures. The cell proangiogenic properties was analysed in vivo, in a hindlimb ischemia model. Perfusion of lower limbs and functional tests were assessed for 28 days after cell infusion. Muscle histological analysis (neoangiogenesis, arteriogenesis and muscle repair) was performed. RESULTS: S-MSCs can be obtained from CLI-patients BMCs. They do not express endothelial specific markers but can be distinguished from MSCs by their secretome. S-MSCs have the ability to form tube-like structures and, in vivo, to induce blood flow recovery. No amputation was observed in S-MSCs treated mice. Functional tests showed improvement in treated groups with a superiority of MSCs and S-MSCs. In muscles, CD31+ and αSMA+ labelling were the highest in S-MSCs treated mice. S-MSCs induced the highest muscle repair. CONCLUSIONS: S-MSCs exert angiogenic potential probably mediated by a paracrine mechanism. Their administration is associated with flow recovery, limb salvage and muscle repair. The secretome from S-MSCs or secretome-derived products may have a strong potential in vessel regeneration and muscle repair. Trial registration NCT00533104.


Asunto(s)
Medios de Cultivo/farmacología , Células Endoteliales/citología , Extremidades/irrigación sanguínea , Isquemia/terapia , Células Madre Mesenquimatosas/citología , Adulto , Anciano , Animales , Arterias/crecimiento & desarrollo , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Extremidades/patología , Femenino , Miembro Posterior/irrigación sanguínea , Humanos , Isquemia/patología , Masculino , Trasplante de Células Madre Mesenquimatosas , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Músculos/irrigación sanguínea , Músculos/patología , Neovascularización Fisiológica , Organogénesis , Flujo Sanguíneo Regional
9.
Cytotherapy ; 19(2): 299-310, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27914820

RESUMEN

BACKGROUND: Cell therapy has been proposed as a salvage limb procedure in critical limb ischemia (CLI). In spite of the fact that clinical trials found some efficacy, the mechanism of action remains elusive. The objective of this study was to characterize two autologous cell therapy products (CTPs) obtained from patients with advanced peripheral arterial disease. METHODS: Bone marrow (BM-CTPs) (n = 20) and CTPs obtained by non-mobilized cytapheresis (peripheral blood [PB]-CTPs) (n = 20) were compared. CTPs were characterized by their cell composition, by the quantification of endothelial progenitor cells (EPCs) and mesenchymal stromal cells (MSCs) and by transcriptomic profiling. The angiogenic profile and the 6-month outcome of CLI patients are described. RESULTS: Patients presented inflammation syndrome and high levels of CXCL12, soluble stem cell factor and granulocyte colony-stimulating factor, whereas granulocyte macrophage colony-stimulating factor was low. Circulating CD34+ cells represented rare events. BM and PB-CTPs were heterogeneous. Mature cells and colony-forming unit-endothelial cells were in higher concentration in PB-CTPs, whereas CD34+ stem cells and EPCs were more abundant in BM-CTPs. MSCs were identified in both CTPs. Transcriptomic profiling revealed the strong angiogenic potential of BM-CTPs. Transcutaneous partial pressure of oxygen, C-reative protein and neutrophil content in CTPs are predictive of the clinical outcome at 6 months. DISCUSSION: Transcriptomic allows an accurate characterization of CTPs. BM-CTPs have the richest content in terms of stem cells and transcriptome. The high content of mature cells in PB-CTPs means that they work via a paracrine mechanism. The clinical outcome indicates the deleterious influence the patients' status and the limits of an autologous approach. In this respect, MSCs may allow an allogenic strategy.


Asunto(s)
Células de la Médula Ósea/citología , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Enfermedad Crítica/terapia , Extremidades/irrigación sanguínea , Isquemia/terapia , Recuperación del Miembro/métodos , Células Madre de Sangre Periférica/citología , Adulto , Anciano , Anciano de 80 o más Años , Trasplante de Médula Ósea , Citaféresis/métodos , Femenino , Factor Estimulante de Colonias de Granulocitos/farmacología , Humanos , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Persona de Mediana Edad , Enfermedad Arterial Periférica/terapia , Trasplante de Células Madre de Sangre Periférica
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