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1.
Nature ; 569(7755): 236-240, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043745

RESUMO

The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death1,2; however, how inflammation is instigated, its cellular and molecular mediators, and its therapeutic value are poorly defined. Here we use mouse models of atherosclerosis-a major underlying cause of mortality worldwide-to demonstrate that extracellular histone H4-mediated membrane lysis of smooth muscle cells (SMCs) triggers arterial tissue damage and inflammation. We show that activated lesional SMCs attract neutrophils, triggering the ejection of neutrophil extracellular traps that contain nuclear proteins. Among them, histone H4 binds to and lyses SMCs, leading to the destabilization of plaques; conversely, the neutralization of histone H4 prevents cell death of SMCs and stabilizes atherosclerotic lesions. Our data identify a form of cell death found at the core of chronic vascular disease that is instigated by leukocytes and can be targeted therapeutically.


Assuntos
Aterosclerose/patologia , Morte Celular , Membrana Celular/metabolismo , Histonas/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Porosidade , Animais , Artérias/patologia , Membrana Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Histonas/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/patologia , Neutrófilos/citologia , Ligação Proteica/efeitos dos fármacos
2.
Arterioscler Thromb Vasc Biol ; 37(2): 312-315, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28062503

RESUMO

OBJECTIVE: Restenosis as a consequence of arterial injury is aggravated by inflammatory pathways. Here, we investigate the role of the proresolving protein annexin A1 (AnxA1) in healing after wire injury. APPROACH AND RESULTS: Apoe-/- and Apoe-/-Anxa1-/- mice were subjected to wire injury while fed a high-cholesterol diet. Subsequently, localization of AnxA1 and AnxA1 plasma levels were examined. AnxA1 was found to localize within endothelial cells and macrophages in the neointima. Levels of AnxA1 in the plasma and its lesional expression negatively correlated with neointima size, and in the absence of AnxA1, neointima formation was aggravated by the accumulation and proliferation of macrophages. In contrast, reendothelialization and smooth muscle cell infiltration were not affected in Apoe-/-Anxa1-/- mice. CONCLUSIONS: AnxA1 is protective in healing after wire injury and could, therefore, be an attractive therapeutic compound to prevent from restenosis after vascular damage.


Assuntos
Anexina A1/metabolismo , Aterosclerose/metabolismo , Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/metabolismo , Neointima , Animais , Anexina A1/deficiência , Anexina A1/genética , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/patologia , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/patologia , Proliferação de Células , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Predisposição Genética para Doença , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Reepitelização , Transdução de Sinais , Remodelação Vascular , Cicatrização
4.
J Am Coll Cardiol ; 73(23): 2990-3002, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31196457

RESUMO

BACKGROUND: Heart failure following myocardial infarction (MI) remains one of the major causes of death worldwide, and its treatment is a crucial challenge of cardiovascular medicine. An attractive therapeutic strategy is to stimulate endogenous mechanisms of myocardial regeneration. OBJECTIVES: This study evaluates the potential therapeutic treatment with annexin A1 (AnxA1) to induce cardiac repair after MI. METHODS: AnxA1 knockout (AnxA1-/-) and wild-type mice underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac functionality was assessed by longitudinal echocardiographic measurements. Histological, fluorescence-activated cell sorting, dot blot analysis, and in vitro/ex vivo studies were used to assess the myocardial neovascularization, macrophage content, and activity in response to AnxA1. RESULTS: AnxA1-/- mice showed a reduced cardiac functionality and an expansion of proinflammatory macrophages in the ischemic area. Cardiac macrophages from AnxA1-/- mice exhibited a dramatically reduced ability to release the proangiogenic mediator vascular endothelial growth factor (VEGF)-A. However, AnxA1 treatment enhanced VEGF-A release from cardiac macrophages, and its delivery in vivo markedly improved cardiac performance. The positive effect of AnxA1 treatment on cardiac performance was abolished in wild-type mice transplanted with bone marrow derived from Cx3cr1creERT2Vegfflox/flox or in mice depleted of macrophages. Similarly, cardioprotective effects of AnxA1 were obtained in pigs in which full-length AnxA1 was overexpressed by use of a cardiotropic adeno-associated virus. CONCLUSIONS: AnxA1 has a direct action on cardiac macrophage polarization toward a pro-angiogenic, reparative phenotype. AnxA1 stimulated cardiac macrophages to release high amounts of VEGF-A, thus inducing neovascularization and cardiac repair.


Assuntos
Anexina A1/deficiência , Macrófagos/fisiologia , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Neovascularização Fisiológica/fisiologia , Fenótipo , Animais , Anexina A1/genética , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/genética , Miocárdio/patologia
5.
EBioMedicine ; 16: 204-211, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28111237

RESUMO

Increases in plasma LDL-cholesterol have unequivocally been established as a causal risk factor for atherosclerosis. Hence, strategies for lowering of LDL-cholesterol may have immediate therapeutic relevance. Here we study the role of human neutrophil peptide 1 (HNP1) in a mouse model of atherosclerosis and identify its potent atheroprotective effect both upon transgenic overexpression and therapeutic delivery. The effect was found to be due to a reduction of plasma LDL-cholesterol. Mechanistically, HNP1 binds to apolipoproteins enriched in LDL. This interaction facilitates clearance of LDL particles in the liver via LDL receptor. Thus, we here identify a non-redundant mechanism by which HNP1 allows for reduction of LDL-cholesterol, a process that may be therapeutically instructed to lower cardiovascular risk.


Assuntos
Aterosclerose/metabolismo , Hipercolesterolemia/metabolismo , Lipoproteínas LDL/metabolismo , Fígado/metabolismo , alfa-Defensinas/metabolismo , Animais , Apolipoproteínas/sangue , Apolipoproteínas/metabolismo , Aterosclerose/genética , Aterosclerose/prevenção & controle , LDL-Colesterol/sangue , LDL-Colesterol/metabolismo , Feminino , Células Hep G2 , Humanos , Hipercolesterolemia/genética , Hipercolesterolemia/prevenção & controle , Imuno-Histoquímica , Lipoproteínas LDL/sangue , Lipoproteínas LDL/farmacocinética , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Ligação Proteica , Interferência de RNA , Receptores de LDL/genética , Receptores de LDL/metabolismo , alfa-Defensinas/administração & dosagem , alfa-Defensinas/genética
6.
PLoS One ; 10(10): e0141019, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26492161

RESUMO

Atherosclerosis-associated diseases are the main cause of mortality and morbidity in western societies. The progression of atherosclerosis is a dynamic process evolving from early to advanced lesions that may become rupture-prone vulnerable plaques. Acute coronary syndromes are the clinical manifestation of life-threatening thrombotic events associated with high-risk vulnerable plaques. Hyperlipidemic mouse models have been extensively used in studying the mechanisms controlling initiation and progression of atherosclerosis. However, the understanding of mechanisms leading to atherosclerotic plaque destabilization has been hampered by the lack of proper animal models mimicking this process. Although various mouse models generate atherosclerotic plaques with histological features of human advanced lesions, a consensus model to study atherosclerotic plaque destabilization is still lacking. Hence, we studied the degree and features of plaque vulnerability in different mouse models of atherosclerotic plaque destabilization and find that the model based on the placement of a shear stress modifier in combination with hypercholesterolemia represent with high incidence the most human like lesions compared to the other models.


Assuntos
Aterosclerose/patologia , Hipercolesterolemia/patologia , Hipertensão Renovascular/patologia , Placa Aterosclerótica/patologia , Animais , Apolipoproteínas E/genética , Artéria Carótida Primitiva/patologia , Artéria Carótida Primitiva/cirurgia , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Feminino , Masculino , Camundongos , Camundongos Knockout , Placa Aterosclerótica/classificação , Artéria Renal/patologia , Artéria Renal/cirurgia , Estresse Mecânico
7.
Sci Transl Med ; 7(317): 317ra196, 2015 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-26659570

RESUMO

In acute and chronic inflammation, neutrophils and platelets, both of which promote monocyte recruitment, are often activated simultaneously. We investigated how secretory products of neutrophils and platelets synergize to enhance the recruitment of monocytes. We found that neutrophil-borne human neutrophil peptide 1 (HNP1, α-defensin) and platelet-derived CCL5 form heteromers. These heteromers stimulate monocyte adhesion through CCR5 ligation. We further determined structural features of HNP1-CCL5 heteromers and designed a stable peptide that could disturb proinflammatory HNP1-CCL5 interactions. This peptide attenuated monocyte and macrophage recruitment in a mouse model of myocardial infarction. These results establish the in vivo relevance of heteromers formed between proteins released from neutrophils and platelets and show the potential of targeting heteromer formation to resolve acute or chronic inflammation.


Assuntos
Plaquetas/metabolismo , Quimiocina CCL5/metabolismo , Monócitos/metabolismo , Neutrófilos/metabolismo , Multimerização Proteica , alfa-Defensinas/metabolismo , Adesão Celular , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Monócitos/citologia , Miocárdio/citologia , Neutrófilos/citologia , Ligação Proteica
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