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1.
Am J Physiol Cell Physiol ; 311(6): C975-C984, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27760754

RESUMO

Vascular smooth muscle cell (SMC) migration is an essential step involved in neointimal formation in restenosis and atherosclerosis. Lysophosphatidic acid (LPA) is a bioactive component of oxidized low-density lipoprotein and is produced by activated platelets, implying that LPA influences vascular remodeling. Our previous study revealed that matricellular protein CCN1, a prominent extracellular matrix (ECM) protein, mediates LPA-induced SMC migration in vitro. Here we examined the role of CCN1 in LPA-induced neointimal formation. By using LPA infusion of carotid artery in a mouse model, we demonstrated that LPA highly induced CCN1 expression (approximately six- to sevenfold) in neointimal lesions. Downregulation of CCN1 expression with the specific CCN1 siRNA in carotid arteries blocked LPA-induced neointimal formation, indicating that CCN1 is essential in LPA-induced neointimal formation. We then used LPA receptor knockout (LPA1-/-, LPA2-/-, and LPA3-/-) mice to examine LPA receptor function in CCN1 expression in vivo and in LPA-induced neointimal formation. Our data reveal that LPA1 deficiency, but not LPA2 or LPA3 deficiency, prevents LPA-induced CCN1 expression in vivo in mouse carotid arteries. We also observed that LPA1 deficiency blunted LPA infusion-induced neointimal formation, indicating that LPA1 is the major mediator for LPA-induced vascular remodeling. Our in vivo model of LPA-induced neointimal formation established a key role of the ECM protein CCN1 in mediating LPA-induced neointimal formation. Our data support the notion that the LPA1-CCN1 axis may be the central control for SMC migration and vascular remodeling. CCN1 may serve as an important vascular disease marker and potential target for vascular therapeutic intervention.


Assuntos
Artéria Carótida Primitiva/efeitos dos fármacos , Artéria Carótida Primitiva/metabolismo , Proteína Rica em Cisteína 61/metabolismo , Lisofosfolipídeos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Neointima/induzido quimicamente , Neointima/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Proteínas da Matriz Extracelular/metabolismo , Feminino , Lipoproteínas LDL/metabolismo , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo
2.
J Biol Chem ; 289(9): 5774-83, 2014 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-24371135

RESUMO

Lysophosphatidic acid (LPA), a potent bioactive lipid found in atherosclerotic lesions, markedly induces smooth muscle cell (SMC) migration, which is an important process in atherogenesis. Therefore, understanding the mechanism of LPA-induced SMC migration is important. Several microarray databases suggest that the matricellular protein Cyr61 is highly induced by LPA. We hypothesized that Cyr61 mediates LPA-induced cell migration. Our data show that LPA induced temporal and spatial expression of Cyr61, which promptly accumulated in the cellular Golgi apparatus and then translocated to the extracellular matrix. Cyr61 antibody blockade and siRNA inhibition both diminished LPA-induced SMC migration, indicating a novel regulatory role of Cyr61. SMCs derived from LPA receptor 1 (LPA1) knock-out mice lack the ability of Cyr61 induction and cell migration, supporting the concept that LPA1 is required for Cyr61 expression and migration. By contrast, PPARγ was not found to be involved in LPA-mediated effects. Furthermore, focal adhesion kinase (FAK), a nonreceptor tyrosine kinase important for regulating cell migration, was activated by LPA at a late time frame coinciding with Cyr61 accumulation. Interestingly, knockdown of Cyr61 blocked LPA-induced FAK activation, indicating that an LPA-Cyr61-FAK axis leads to SMC migration. Our results further demonstrate that plasma membrane integrins α6ß1 and ανß3 transduced the LPA-Cyr61 signal toward FAK activation and migration. Taken together, these data reveal that de novo Cyr61 in the extracellular matrix bridges LPA and integrin pathways, which in turn, activate FAK, leading to cell migration. The current study provides new insights into mechanisms underlying cell migration-related disorders, including atherosclerosis, restenosis, and cancers.


Assuntos
Movimento Celular/fisiologia , Proteína Rica em Cisteína 61/metabolismo , Integrina alfa6beta1/metabolismo , Integrina alfaVbeta3/metabolismo , Lisofosfolipídeos/metabolismo , Miócitos de Músculo Liso/metabolismo , Animais , Células Cultivadas , Proteína Rica em Cisteína 61/genética , Ativação Enzimática/fisiologia , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Integrina alfa6beta1/genética , Integrina alfaVbeta3/genética , Lisofosfolipídeos/genética , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/citologia , PPAR gama/genética , PPAR gama/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo
3.
Am J Physiol Heart Circ Physiol ; 303(11): H1344-52, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23001835

RESUMO

Histamine, an inflammatory mediator, has been shown to influence the pathogenesis of vascular wall cells. However, the molecular basis of its influence is not well understood. Our data reveal that histamine markedly induces protein kinase D (PKD) activation in human aortic smooth muscle cells. PKD belongs to a family of serine/threonine protein kinases, and its function in vascular disease is largely unknown. Our data show that histamine-induced PKD phosphorylation is dependent on the activation of histamine receptor 1 and protein kinase C (PKC). To determine the role of PKD in the histamine pathway, we employed a small-interfering RNA approach to downregulate PKD expression and found that PKD1 and PKD2 are key mediators for expression of tissue factor (TF), which is the key initiator of blood coagulation and is important for thrombosis. Our results show that PKD2 predominantly mediates histamine-induced TF expression via the p38 mitogen-activated protein kinase (MAPK) pathway, whereas PKD1 mediates histamine-induced TF expression through a p38 MAPK-independent pathway. We demonstrate that histamine induces TF expression via the PKC-dependent PKD activation. Our data provide the first evidence that PKD is a new component in histamine signaling in live cells and that PKD has a novel function in the histamine signaling pathway leading to gene expression, as evidenced by TF expression. Importantly, our data reveal a regulatory link from histamine to PKD and TF, providing new insights into the mechanisms of coagulation and the development of atherothrombosis.


Assuntos
Aorta/metabolismo , Histamina/farmacologia , Músculo Liso Vascular/metabolismo , Proteína Quinase C/metabolismo , Tromboplastina/metabolismo , Aorta/patologia , Coagulação Sanguínea/fisiologia , Células Cultivadas , Humanos , Técnicas In Vitro , Isoenzimas/metabolismo , Músculo Liso Vascular/patologia , Fosforilação , Receptores Histamínicos/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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