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1.
J Cell Mol Med ; 24(5): 3139-3148, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31970902

RESUMO

Macrophage activation participates in the pathogenesis of pulmonary inflammation. As a coenzyme, vitamin B6 (VitB6) is mainly involved in the metabolism of amino acids, nucleic acids, glycogen and lipids. We have previously reported that activation of AMP-activated protein kinase (AMPK) produces anti-inflammatory effects both in vitro and in vivo. Whether VitB6 via AMPK activation prevents pulmonary inflammation remains unknown. The model of acute pneumonia was induced by injecting mice with lipopolysaccharide (LPS). The inflammation was determined by measuring the levels of interleukin-1 beta (IL-1ß), IL-6 and tumour necrosis factor alpha (TNF-α) using real time PCR, ELISA and immunohistochemistry. Exposure of cultured primary macrophages to VitB6 increased AMP-activated protein kinase (AMPK) Thr172 phosphorylation in a time/dose-dependent manner, which was inhibited by compound C. VitB6 downregulated the inflammatory gene expressions including IL-1ß, IL-6 and TNF-α in macrophages challenged with LPS. These effects of VitB6 were mirrored by AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). However, VitB6 was unable to inhibit LPS-induced macrophage activation if AMPK was in deficient through siRNA-mediated approaches. Further, the anti-inflammatory effects produced by VitB6 or AICAR in LPS-treated macrophages were abolished in DOK3 gene knockout (DOK3-/- ) macrophages, but were enhanced in macrophages if DOK3 was overexpressed. In vivo studies indicated that administration of VitB6 remarkably inhibited LPS-induced both systemic inflammation and acute pneumonia in wild-type mice, but not in DOK3-/- mice. VitB6 prevents LPS-induced acute pulmonary inflammation in mice via the inhibition of macrophage activation.

2.
J Cell Mol Med ; 24(3): 2319-2329, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31880857

RESUMO

Cardiac fibrosis is a key factor to determine the prognosis in patient with myocardial infarction (MI). The aim of this study is to investigate whether the transcriptional factor paired-related homeobox 2 (Prrx2) regulates Wnt5a gene expression and the role in myocardial fibrosis following MI. The MI surgery was performed by ligation of left anterior descending coronary artery. Cardiac remodelling was assessed by measuring interstitial fibrosis performed with Masson staining. Cell differentiation was examined by analysis the expression of alpha-smooth muscle actin (α-SMA). Both Prrx2 and Wnt5a gene expressions were up-regulated in mice following MI, accompanied with increased mRNA and protein levels of α-SMA, collagen I and collagen III, compared to mice with sham surgery. Adenovirus-mediated gene knock down of Prrx2 increased survival rate, alleviated cardiac fibrosis, decreased infarction sizes and improved cardiac functions in mice with MI. Importantly, inhibition of Prrx2 suppressed ischaemia-induced Wnt5a gene expression and Wnt5a signalling. In cultured cardiac fibroblasts, TGF-ß increased gene expressions of Prrx2 and Wnt5a, and induced cell differentiations, which were abolished by gene silence of either Prrx2 or Wnt5a. Further, overexpression of Prrx2 or Wnt5a mirrored the effects of TGF-ß on cell differentiations of cardiac fibroblasts. Gene silence of Wnt5a also ablated cell differentiations induced by Prrx2 overexpression in cardiac fibroblasts. Mechanically, Prrx2 was able to bind with Wnt5a gene promoter to up-regulate Wnt5a gene expression. In conclusions, targeting Prrx2-Wnt5a signalling should be considered to improve cardiac remodelling in patients with ischaemic heart diseases.

3.
PLoS One ; 14(8): e0220845, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31369643

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0098047.].

4.
Hypertension ; 72(5): 1189-1199, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354818

RESUMO

Abdominal aortic aneurysm (AAA) is a common vascular degenerative disease. PARP-1 (poly[ADP-ribose] polymerase 1) is a nuclear enzyme, which plays a critical role in vascular diseases. We hypothesized that PARP-1 inhibition might have protective effects on AAA. In vivo, Ang II (angiotensin II) was continuously infused by a micropump for 28 days to induce AAA in mice. In vitro, aortic endothelial cells and smooth muscle cells were stimulated by Ang II for 24 hours. Ang II infusion increased PARP-1 expression and activity and successfully induced AAA formation partly with a hemorrhage in ApoE-/- mice. Genetic deletion of PARP-1 markedly reduced the AAA incidence, abdominal aortic diameter, macrophage infiltration, ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular adhesion molecule 1) expression, and MMP (matrix metalloproteinase) expression, as well as MMP activity; but increased smooth muscle cells content and collagens expression in AAA. PARP-1 inhibition by PJ-34 also exerted a protective effect on AAA in mice. In aortic endothelial cells, Ang II-induced oxidative stress and DNA damage, resulting in increased PARP-1 expression and activity. Compared with the control, Ang II increased TNF-α (tumor necrosis factor α) and IL-6 (interleukin-6) secretions, ICAM-1 expression and THP-1 (human acute monocytic leukemia cell line) cells adhesion, while PARP-1 inhibition by siRNA reduced the inflammatory response probably through inhibition of the phosphorylation of ERK (extracellular signal-regulated kinase), NF-κB (nuclear factor-κB), and Akt signaling pathways. In smooth muscle cells, Ang II promoted cell migration, proliferation, and apoptosis, reduced collagens expression, but increased MMPs expression, while PARP-1 deletion alleviated these effects partly by reducing NF-κB-targeted MMP-9 expression. PARP-1 inhibition might be a feasible strategy for the treatment of AAA.


Assuntos
Aneurisma da Aorta Abdominal/prevenção & controle , Pressão Sanguínea/fisiologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Colágeno/metabolismo , Citocinas/metabolismo , Dano ao DNA/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/genética , RNA Interferente Pequeno , Transdução de Sinais/efeitos dos fármacos
5.
J Mol Cell Cardiol ; 114: 334-344, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29269260

RESUMO

Peptidyl-prolyl isomerase Pin1 has been reported to be associated with endothelial dysfunction. However, the role of smooth muscle Pin1 in the vascular system remains unclear. Here, we examined the potential function of Pin1 in smooth muscle cells (SMCs) and its contribution to abdominal aortic aneurysm (AAA) pathogenesis. The level of Pin1 expression was found to be elevated in human AAA tissues and mainly localized to SMCs. We constructed smooth muscle-specific Pin1 knockout mice to explore the role of this protein in AAA formation and to elucidate the underlying mechanisms. AAA formation and elastin degradation were hindered by Pin1 depletion in the angiotensin II-induced mouse model. Pin1 depletion reversed the angiotensin II-induced pro-inflammatory and synthetic SMC phenotype switching via the nuclear factor (NF)-κB p65/Klf4 axis. Moreover, Pin1 depletion inhibited the angiotensin II-induced matrix metalloprotease activities. Mechanically, Pin1 deficiency destabilized NF-κB p65 by promoting its polyubiquitylation. Further, we found STAT1/3 bound to the Pin1 promoter, revealing that activation of STAT1/3 was responsible for the increased expression of Pin1 under angiotensin II stimulation. Thus, these results suggest that Pin1 regulates pro-inflammatory and synthetic SMC phenotype switching and could be a novel therapeutic target to limit AAA pathogenesis.


Assuntos
Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/enzimologia , Apolipoproteínas E/deficiência , Peptidilprolil Isomerase de Interação com NIMA/deficiência , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/prevenção & controle , Apolipoproteínas E/metabolismo , Movimento Celular , Proliferação de Células , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Peptidilprolil Isomerase de Interação com NIMA/genética , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Fenótipo , Regiões Promotoras Genéticas/genética , Fatores de Transcrição STAT/metabolismo , Regulação para Cima
6.
PLoS One ; 9(9): e108806, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25268972

RESUMO

BACKGROUND: In the clinic, variations in circadian rhythm are evident in patients with cardiovascular disease, and the risk of cardiovascular events increases when rhythms are disrupted. In this study, we focused on the role of the circadian gene period2 (per2) in mobilization and function of endothelial progenitor cells (EPCs) in vitro and in vivo after myocardial infarction (MI) in mice. METHODS AND RESULTS: MI was produced by surgical ligation of the left anterior descending coronary artery in mice with and without per2 deficiency. Trans-thoracic echocardiography was used to evaluate cardiac function in mice. Per2-/- mice with MI showed decreased cardiac function and increased infarct size. The number of CD34+ cells and capillary density were decreased in the myocardium of per2-/- mice on immunohistochemistry. Flow cytometry revealed decreased number of circulating EPCs in per2-/- mice after MI. In vitro, per2-/- EPCs showed decreased migration and tube formation capacity under hypoxia. Western blot analysis revealed inhibited activation of extracellular signal-regulated kinase and Akt signaling in the bone marrow of per2-/- mice and inhibited PI3K/Akt expression in per2-/- EPCs under hypoxia. CONCLUSIONS: Per2 modulates EPC mobilization and function after MI, which is important to recovery after MI in mice.


Assuntos
Hipóxia Celular , Células Progenitoras Endoteliais/metabolismo , Proteínas Circadianas Period/metabolismo , Animais , Células da Medula Óssea/metabolismo , Movimento Celular , Células Cultivadas , Células Progenitoras Endoteliais/citologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas Circadianas Period/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
7.
PLoS One ; 9(9): e107851, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25233229

RESUMO

BACKGROUND: Ectopic angiogenesis within the intima and media is considered to be a hallmark of advanced vulnerable atherosclerotic lesions. Some studies have shown that specific matrix metalloproteinases (MMPs) might play different roles in angiogenesis. Therefore, we investigated the predominant effects of specific MMPs in intraplaque angiogenesis and plaque instability in a rabbit model of atherosclerosis. METHODS AND RESULTS: New Zealand rabbits underwent balloon injury of the abdominal artery and ingestion of a high-cholesterol (1%) diet to establish an atherosclerotic animal model. At weeks 4, 6, 8, 10, and 12 after balloon injury, five rabbits were euthanized and the abdominal aorta was harvested. Blood lipid analysis, intravascular ultrasound imaging, pathologic and immunohistochemical expression studies, and western blotting were performed. From weeks 4 to 12, the expression of MMP-1, -2, -3, and -9 and vascular endothelial growth factor A (VEGF-A) increased with atherosclerotic plaque development in the abdominal aorta, while the expression of MMP-14 substantially decreased. The vulnerability index (VI) gradually increased over time. Intraplaque neovessels appeared at week 8. The microvessel density (MVD) was greater at week 12 than at week 8. The VI, MVD, and VEGF-A level were positively correlated with the MMP-1, -2,-3, and -9 levels within plaques. Negative correlations were noted between the MMP-14 level and the VI, MVD, and VEGF-A level. CONCLUSION: Upregulation of MMP-1, -2, -3, and -9 and downregulation of MMP-14 may contribute to intraplaque angiogenesis and plaque instability at the advanced stage of atherosclerosis in rabbits.


Assuntos
Aterosclerose/enzimologia , Metaloproteinases da Matriz/fisiologia , Neovascularização Patológica/enzimologia , Placa Aterosclerótica/enzimologia , Animais , Aterosclerose/fisiopatologia , Masculino , Microvasos/patologia , Microvasos/fisiopatologia , Placa Aterosclerótica/fisiopatologia , Coelhos
8.
J Cell Mol Med ; 18(8): 1599-611, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24889822

RESUMO

Autophagic dysfunction is observed in diabetes mellitus. Resveratrol has a beneficial effect on diabetic cardiomyopathy. Whether the resveratrol-induced improvement in cardiac function in diabetes is via regulating autophagy remains unclear. We investigated the mechanisms underlying resveratrol-mediated protection against heart failure in diabetic mice, with a focus on the role of sirtuin 1 (SIRT1) in regulating autophagic flux. Diabetic cardiomyopathy in mice was induced by streptozotocin (STZ). Long-term resveratrol treatment improved cardiac function, ameliorated oxidative injury and reduced apoptosis in the diabetic mouse heart. Western blot analysis revealed that resveratrol decreased p62 protein expression and promoted SIRT1 activity and Rab7 expression. Inhibiting autophagic flux with bafilomycin A1 increased diabetic mouse mortality and attenuated resveratrol-induced down-regulation of p62, but not SIRT1 activity or Rab7 expression in diabetic mouse hearts. In cultured H9C2 cells, redundant or overactive H2O2 increased p62 and cleaved caspase 3 expression as well as acetylated forkhead box protein O1 (FOXO1) and inhibited SIRT1 expression. Sirtinol, SIRT1 and Rab7 siRNA impaired the resveratrol amelioration of dysfunctional autophagic flux and reduced apoptosis under oxidative conditions. Furthermore, resveratrol enhanced FOXO1 DNA binding at the Rab7 promoter region through a SIRT1-dependent pathway. These results highlight the role of the SIRT1/FOXO1/Rab7 axis in the effect of resveratrol on autophagic flux in vivo and in vitro, which suggests a therapeutic strategy for diabetic cardiomyopathy.


Assuntos
Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Estilbenos/farmacologia , Acetilação , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Células Cultivadas , Diabetes Mellitus Experimental/tratamento farmacológico , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/patologia , Oxirredução , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Resveratrol , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Sirtuína 1/metabolismo , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
9.
PLoS One ; 9(6): e98047, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24887083

RESUMO

BACKGROUND: It has been demonstrated that Tongxinluo (TXL), a traditional Chinese medicine compound, improves ischemic heart disease in animal models via vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). The present study aimed to investigate whether TXL protects against pressure overload-induced heart failure in mice and explore the possible mechanism of action. METHODS AND RESULTS: Transverse aortic constriction (TAC) surgery was performed in mice to induce heart failure. Cardiac function was evaluated by echocardiography. Myocardial pathology was detected using hematoxylin and eosin or Masson trichrome staining. We investigated cardiomyocyte ultrastructure using transmission electron microscopy. Angiogenesis and oxidative stress levels were determined using CD31 and 8-hydroxydeoxyguanosine immunostaining and malondialdehyde assay, respectively. Fetal gene expression was measured using real-time PCR. Protein expression of VEGF, phosphorylated (p)-VEGF receptor 2 (VEGFR2), p-phosphatidylinositol 3-kinase (PI3K), p-Akt, p-eNOS, heme oxygenase-1 (HO-1), and NADPH oxidase 4 (Nox4) were measured with western blotting. Twelve-week low- and high-dose TXL treatment following TAC improved cardiac systolic and diastolic function and ameliorated left ventricular hypertrophy, fibrosis, and myocardial ultrastructure derangement. Importantly, TXL increased myocardial capillary density significantly and attenuated oxidative stress injury in failing hearts. Moreover, TXL upregulated cardiac nitrite content and the protein expression of VEGF, p-VEGFR2, p-PI3K, p-Akt, p-eNOS, and HO-1, but decreased Nox4 expression in mouse heart following TAC. CONCLUSION: Our findings indicate that TXL protects against pressure overload-induced heart failure in mice. Activation of the VEGF/Akt/eNOS signaling pathway might be involved in TXL improvement of the failing heart.


Assuntos
Cardiotônicos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Capilares/efeitos dos fármacos , Capilares/patologia , Capilares/fisiopatologia , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Cardiotônicos/farmacologia , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Miocárdio/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ultrassonografia
10.
J Cell Mol Med ; 18(5): 907-18, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24621388

RESUMO

Cellular therapeutic neovascularization has been successfully performed in clinical trials for patients with ischaemia diseases. Despite the vast knowledge of cardiovascular disease and circadian biology, the role of the circadian clock in regulating angiogenesis in myocardial infarction (MI) remains poorly understood. In this study, we aimed to investigate the role and underlying mechanisms of Period 2 (Per2) in endothelial progenitor cell (EPC) function. Flow cytometry revealed lower circulating EPC proportion in per2(-/-) than in wild-type (WT) mice. PER2 was abundantly expressed in early EPCs in mice. In vitro, EPCs from per2(-/-) mice showed impaired proliferation, migration, tube formation and adhesion. Western blot analysis demonstrated inhibited PI3k/Akt/FoxO signalling and reduced C-X-C chemokine receptor type 4 (CXCR4) protein level in EPCs of per2(-/-) mice. The impaired proliferation was blocked by activated PI3K/Akt/FoxO signalling. Direct interaction of CXCR4 and PER2 was detected in WT EPCs. To further study the effect of per2 on in vivo EPC survival and angiogenesis, we injected saline or DiI-labelled WT or per2(-/-) EPC intramyocardially into mice with induced MI. Per2(-/-) reduced the retention of transplanted EPCs in the myocardium, which was associated with significantly reduced DiI expression in the myocardium of MI mice. Decreased angiogenesis in the myocardium of per2(-/-) EPC-treated mice coincided with decreased LV function and increased infarct size in the myocardium. Per2 may be a key factor in maintaining EPC function in vitro and in therapeutic angiogenesis in vivo.


Assuntos
Células Progenitoras Endoteliais/citologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Neovascularização Fisiológica , Proteínas Circadianas Period/metabolismo , Animais , Apoptose , Adesão Celular , Contagem de Células , Movimento Celular , Proliferação de Células , Células Cultivadas , Fatores de Transcrição Forkhead/metabolismo , Testes de Função Cardíaca , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/patologia , Proteínas Circadianas Period/deficiência , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores CXCR4/metabolismo , Transplante de Células-Tronco , Análise de Sobrevida
11.
Artigo em Inglês | MEDLINE | ID: mdl-24069057

RESUMO

Background. Myocardial infarction (MI) is a major cause of morbidity and mortality in the world. Tongxinluo (TXL) is a traditional Chinese compound prescription which has cardioprotective functions. The present study was aimed to determine the effect of TXL on postischemic cardiac dysfunction and cardiac remodeling and to elucidate the underlying mechanisms. Methods and Results. MI was performed by ligation of left anterior descending coronary artery (LAD) in male adult mice. Mice were randomly divided into four groups: (1) sham group (Sham); (2) MI-control group (Control); (3) MI-low dose TXL group (TXL-L); and (4) MI-high dose TXL (TXL-H) group. Compared with the control group, TXL treatment restored cardiac function, increased revascularization, attenuated cardiomyocyte apoptosis, and reduced interstitial fibrosis. TXL treatment increased the phosphorylation of Akt, extracellular signal regulated kinase (ERK), and endothelial nitric oxide synthase (eNOS); the expression of phosphatidylinositol3-kinase (PI3K), hypoxia-inducible factors 1 α (HIF-1 α ), and vascular endothelial growth factor (VEGF); and the DNA binding activity of HIF-1 α after MI. Conclusion. TXL may improve cardiac function and ameliorate cardiac remodeling by increasing neovascularization through enhancing the phosphorylation of Akt and ERK, the expression and activity of HIF-1 α , and the protein level of VEGF and p-eNOS.

12.
PLoS One ; 8(1): e54303, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23349848

RESUMO

OBJECTIVES: Endothelial progenitor cells (EPCs) can be used to repair tissues after myocardial infarction (MI) but EPC activators have adverse reactions. Rehmannia glutinosa is a herb used in traditional Chinese medicine, which can promote bone-marrow proliferation and protect the ischemic myocardium. We investigated the effects of Rehmannia glutinosa extract (RGE) on EPCs in a rat model of MI. METHODS: A total of 120 male Wistar rats were randomized to 2 groups (n=60 each) for treatment: high-dose RGE (1.5 g·kg(-1)·day(-1) orally) for 8 weeks, then left anterior descending coronary artery ligation, mock surgery or no treatment, then RGE orally for 4 weeks; or normal saline (NS) as the above protocol. The infarct region of the left ventricle was assessed by serial sectioning and morphology. EPCs were evaluated by number and function. Protein and mRNA levels of CD133, vascular endothelial growth factor receptor 2 (VEGFR2), chemokine C-X-C motif receptor 4 (CXCR4), stromal cell-derived factor-1α (SDF-1α) were measured by immunohistochemistry, Western blot and quantitative PCR analysis. RESULTS: RGE significantly improved left ventricular function, decreased the ischemic area and the apoptotic index in the infarct myocardium, also decreased the concentration of serum cardiac troponin T and brain natriuretic peptide at the chronic stage after MI (from week 2 to week 4). RGE increased EPC number, proliferation, migration and tube-formation capacity. It was able to up-regulate the expression of angiogenesis-associated ligand/receptor, including CD133, VEGFR2 and SDF-1α/CXCR4. In vitro, the effect of RGE on SDF-1α/CXCR4 cascade was reversed by the CXCR4 specific antagonist AMD3100. CONCLUSION: RGE may enhance the mobilization, migration and therapeutic angiogenesis of EPCs after MI by activating the SDF-1α/CXCR4 cascade.


Assuntos
Quimiocina CXCL12/metabolismo , Células Endoteliais/efeitos dos fármacos , Infarto do Miocárdio/prevenção & controle , Extratos Vegetais/farmacologia , Receptores CXCR4/metabolismo , Rehmannia/química , Células-Tronco/efeitos dos fármacos , Antígeno AC133 , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Western Blotting , Quimiocina CXCL12/genética , Células Endoteliais/metabolismo , Expressão Gênica/efeitos dos fármacos , Glicoproteínas/genética , Glicoproteínas/metabolismo , Imuno-Histoquímica , Masculino , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Peptídeos/genética , Peptídeos/metabolismo , Fitoterapia , Distribuição Aleatória , Ratos , Ratos Wistar , Receptores CXCR4/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Células-Tronco/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
13.
Psychosom Med ; 74(6): 604-11, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22753638

RESUMO

OBJECTIVES: Chronic psychological stress is associated with an increased risk of atherosclerosis in humans. Experimental studies using various stress models have yielded controversial results. This study investigated the effects of unpredictable chronic mild stress (UCMS) on atherogenesis in New Zealand white rabbits. METHODS: Rabbits were fed with a cholesterol-enriched (1%) diet for 4 to 16 weeks, with or without concomitant UCMS treatment. Atherosclerosis was assessed in the abdominal aorta by serial sectioning and morphological analysis. Expressions of inflammatory factors were measured with immunohistochemistry and quantitative polymerase chain reaction. Serum nitrate/nitrite levels were determined with Griess assay, and corticosterone and inflammatory markers were determined using enzyme-linked immunosorbent assay. RESULTS: High-cholesterol feeding resulted in hypercholesterolemia and formation of atherosclerotic plaques in the aorta. UCMS exposure significantly increased the plaque size (p = .003) and decreased the plaque stability (decreased the contents of collagen and smooth muscle and increased the amount of macrophage and matrix metalloproteinases). The proatherogenic effects of UCMS were unrelated to changes in serum cholesterol level but accompanied by increased blood pressure (p < .001) and vascular inflammation (up-regulation of tumor necrosis factor α, C-reactive protein, and monocyte chemoattractant protein 1, all p values < .01). Serum concentrations of nitrate/nitrite were lower in UCMS-treated animals (p = .01). Vessels from UCMS-treated animals exhibited augmented phosphorylation of p38 and c-Jun N-terminal kinase and activation of nuclear factor κB. CONCLUSIONS: Chronic psychological stress may contribute to the development of atherosclerosis by enhancing vascular inflammation and decreasing endothelial nitric oxide bioavailability.


Assuntos
Aorta Abdominal/patologia , Aterosclerose/etiologia , Dieta Aterogênica/efeitos adversos , Placa Aterosclerótica/patologia , Estresse Psicológico/complicações , Animais , Aorta Abdominal/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Pressão Sanguínea/fisiologia , Proteína C-Reativa/metabolismo , Doença Crônica , Corticosterona/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Inflamação/metabolismo , Masculino , Nitratos/sangue , Óxido Nítrico Sintase Tipo III/metabolismo , Nitritos/sangue , Placa Aterosclerótica/metabolismo , Reação em Cadeia da Polimerase , Coelhos , Distribuição Aleatória , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Fator de Necrose Tumoral alfa/metabolismo
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