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1.
J Biol Chem ; 288(44): 31635-45, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24003215

RESUMO

Monocyte infiltration and macrophage formation are pivotal steps in atherosclerosis and plaque vulnerability. Gremlin-1/Drm is crucial in embryo-/organogenesis and has been shown to be expressed in the adult organism at sites of arterial injury and to inhibit monocyte migration. The purpose of the present study was to evaluate and characterize the role of Gremlin-1 in atherosclerosis. Here we report that Gremlin-1 is highly expressed primarily by monocytes/macrophages in aortic atherosclerotic lesions of ApoE(-/-) mice and is secreted from activated monocytes and during macrophage development in vitro. Gremlin-1 reduces macrophage formation by inhibiting macrophage migration inhibitory factor (MIF), a cytokine critically involved in atherosclerotic plaque progression and vulnerability. Gremlin-1 binds with high affinity to MIF (KD = 54 nm), as evidenced by surface plasmon resonance analysis and co-immunoprecipitation, and reduces MIF-induced release of TNF-α from macrophages. Treatment of ApoE(-/-) mice with a dimeric recombinant fusion protein, mGremlin1-Fc, but not with equimolar control Fc or inactivated mGremlin1-Fc, reduced TNF-α expression, the content of monocytes/macrophages of atherosclerotic lesions, and attenuated atheroprogression. The present data disclose that Gremlin-1 is an endogenous antagonist of MIF and define a role for Gremlin-1/MIF interaction in atherosclerosis.


Assuntos
Apolipoproteínas E , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Oxirredutases Intramoleculares/biossíntese , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/biossíntese , Fatores Inibidores da Migração de Macrófagos/genética , Macrófagos/patologia , Camundongos , Camundongos Knockout , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Fator de Necrose Tumoral alfa/genética
2.
Eur J Hum Genet ; 21(8): 807-15, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23232698

RESUMO

Neutral lipid storage disease comprises a heterogeneous group of inherited disorders characterized by severe accumulation of cytoplasmic triglyceride droplets in several tissues and neutrophils. A novel type of autosomal recessive lipid myopathy due to PNPLA2 mutations was recently described with associated cardiac disease, myopathy and frequent infections, but without ichthyosis. Here we describe the clinical and biochemical characteristics of a long surviving patient and report on four carrier family members with diverse clinical involvement. Interestingly, heterozygous patients show neutral lipid storage in muscle and in the keratocytes of the skin, Jordans' bodies, mild myopathy and frequent infections. Biochemical analysis of fibroblasts obtained from patients revealed increased triglyceride storage and reduced lipid droplet-associated triglyceride hydrolase activity. Together, our data implicate that the wild-type allele cannot fully compensate for the mutated dysfunctional allele of PNPLA2 leading to triglyceride accumulation in muscle and mild myopathy in PNPLA2 mutation carriers. The presence of neutral lipid droplets in the skin in PNPLA2 mutation carriers strengthens the link between NLSD and other neutral lipid storage diseases with ichthyosis.


Assuntos
Heterozigoto , Lipase/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Musculares/genética , Adolescente , Adulto , Criança , Pré-Escolar , Saúde da Família , Feminino , Humanos , Masculino , Microscopia Eletrônica , Músculos/metabolismo , Músculos/ultraestrutura , Mutação , Linhagem
3.
Arterioscler Thromb Vasc Biol ; 32(8): 2017-20, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22701021

RESUMO

OBJECTIVE: Hyperlipidemia is associated with platelet hyperactivity. In the present study, we evaluated the binding of oxidized low-density lipoprotein (oxLDL) on the surface of circulating platelets in patients with stable coronary artery disease and acute coronary syndromes and its possible association with platelet activation. Furthermore, the role of oxLDL binding on platelet adhesion to collagen and endothelial cells in vitro as well as after carotid ligation in mice was investigated. METHODS AND RESULTS: Using flow cytometry, patients with acute coronary syndromes (n=174) showed significantly enhanced oxLDL binding compared with patients with stable coronary artery disease (n=182; P=0.007). Platelet-bound oxLDL positively correlated with the degree of platelet activation (expression of P-selectin and activated fibrinogen receptor; P<0.001 for both). Plasma oxLDL was increased in patients with acute coronary syndromes compared with stable angina pectoris patients. Preincubation of isolated platelets with oxLDL, but not with native LDL, resulted in enhanced platelet adhesion to collagen and activated endothelial cells under high shear stress in vitro, as well as after carotid ligation in C57BL/6J mice and apolipoprotein E(-/-) mice fed a high cholesterol diet. CONCLUSIONS: Increased platelet-bound oxLDL in patients with acute coronary syndromes may play an important role in atherothrombosis, thus providing a potential future therapeutic target.


Assuntos
Síndrome Coronariana Aguda/sangue , Plaquetas/metabolismo , Lipoproteínas LDL/metabolismo , Adesividade Plaquetária , Animais , Apolipoproteínas E/fisiologia , Aterosclerose/etiologia , Células Endoteliais/fisiologia , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Ativação Plaquetária
4.
J Biol Chem ; 287(3): 2168-78, 2012 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-22102277

RESUMO

A mutual relationship exists between metastasizing tumor cells and components of the coagulation cascade. The exact mechanisms as to how platelets influence blood-borne metastasis, however, remain poorly understood. Here, we used murine B16 melanoma cells to observe functional aspects of how platelets contribute to the process of hematogenous metastasis. We found that platelets interfere with a distinct step of the metastasis cascade, as they promote adhesion of melanoma cells to the endothelium in vitro under shear conditions. Constitutively active platelet receptor GPIIb/IIIa (integrin αIIbß3) expressed on Chinese hamster ovary cells promoted melanoma cell adhesion in the presence of fibrinogen, whereas blocking antibodies to aνß3 integrin on melanoma cells or to GPIIb/IIIa significantly reduced melanoma cell adhesion to platelets. Furthermore, using intravital microscopy, we observed functional platelet-melanoma cell interactions, as platelet depletion resulted in significantly reduced melanoma cell adhesion to the injured vascular wall in vivo. Using a mouse model of hematogenous metastasis to the lung, we observed decreased metastasis of B16 melanoma cells to the lung by treatment with a mAb blocking the aν subunit of aνß3 integrin. This effect was significantly reduced when platelets were depleted in vivo. Thus, the engagement of GPIIb/IIIa with aνß3 integrin interaction mediates tumor cell-platelet interactions and highlights how this interaction is involved in hematogenous tumor metastasis.


Assuntos
Plaquetas/metabolismo , Neoplasias da Medula Óssea/metabolismo , Neoplasias da Medula Óssea/secundário , Melanoma/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Animais , Anticorpos Neutralizantes/farmacologia , Plaquetas/patologia , Neoplasias da Medula Óssea/genética , Neoplasias da Medula Óssea/patologia , Células CHO , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Cricetinae , Cricetulus , Feminino , Humanos , Melanoma/genética , Melanoma/patologia , Camundongos , Metástase Neoplásica , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética
5.
Cancer Res ; 71(12): 4096-105, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21593193

RESUMO

Hematogenous dissemination of melanoma is a life-threatening complication of this malignant tumor. Here, we identified junctional adhesion molecule-C (JAM-C) as a novel player in melanoma metastasis to the lung. JAM-C expression was identified in human and murine melanoma cell lines, in human malignant melanoma, as well as in metastatic melanoma including melanoma lung metastasis. JAM-C expressed on both murine B16 melanoma cells as well as on endothelial cells promoted the transendothelial migration of the melanoma cells. We generated mice with inactivation of JAM-C. JAM-C(-/-) mice as well as endothelial-specific JAM-C-deficient mice displayed significantly decreased B16 melanoma cell metastasis to the lung, whereas treatment of mice with soluble JAM-C prevented melanoma lung metastasis. Together, JAM-C represents a novel therapeutic target for melanoma metastasis.


Assuntos
Moléculas de Adesão Celular/fisiologia , Imunoglobulinas/fisiologia , Neoplasias Pulmonares/secundário , Melanoma/patologia , Animais , Células CHO , Moléculas de Adesão Celular/análise , Moléculas de Adesão Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Movimento Celular , Cricetinae , Cricetulus , Células Endoteliais/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica
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