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1.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(3): 209-214, 2019 May 28.
Artigo em Chinês | MEDLINE | ID: mdl-31257800

RESUMO

OBJECTIVE: To investigate the effects of apple polyphenols on pulmonary vascular remodeling in rats with pulmonary arterial hypertension and its mechanism. METHODS: Rats were randomly divided into 4 groups:control (Con) group, monocrotaline (MCT) group, apple polyphenol (APP) group,monocrotaline + apple polyphenol (MCT+APP) group. In Con group, rats received a subcutaneous injection of physical saline. In APP group, rats received intraperitoneal injection of 20 mg/kg APP, every other day. In MCT group, rats received a single subcutaneous injection of MCT(60 mg/kg). In MCT+APP group, rats received subcutaneous injection of 60 mg/kg MCT followed by an intraperitoneal injection of 20 mg/kg APP every other day. All the disposal lasted 3 weeks. Then the PAH-relevant indicators, such as mean pulmonary artery pressure(mPAP), pulmonary vascular resistance(PVR), right ventricular hypertrophy index (RVHI) ,wall thickness (WT%) and wall area (WA%) were tested. After that, the inflammatory pathway related indicators, such as interleukin1(IL-1),interleukin1(IL-6), tumor necrosis factor α(TNF-α), cyclooxygenase 2(COX-2) and myeloperoxidase(MPO) in pulmonary tissue and free intracellular Ca2+ in pulmonary smooth muscle cell(PASMC), content of eNOS and NO in endothelial cells were determined. RESULTS: Compared with the control group, the levels of mPAP, PVR, RVHI, WA%, WT%, and IL-1, IL-6, TNF-α, COX-2, MPO in tissue and the expression of Ca2 + in PASMC of MCT group were increased significantly, while the contents of eNOS and NO in endothelial cells were decreased significantly (P<0.05). Compared with the MCT group, the apple polyphenol treatment could improve the above mentioned situation, and the COX-2 and Ca2+ indicators of the apple polyphenol treatment group were decreased significantly (P<0.05). CONCLUSION: MCT can increase COX-2 expression and intracellular Ca2+ in pulmonary artery smooth muscle cells, decrease the contents of eNOS and NO in endothelial cells, while apple polyphenols can significantly inhibit these effects.


Assuntos
Malus/química , Polifenóis/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Animais , Cálcio/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Monocrotalina , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Artéria Pulmonar/patologia , Distribuição Aleatória , Ratos
2.
Chem Biol Interact ; 311: 108749, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31325423

RESUMO

PURPOSE: Excessive proliferation, migration and anti-apoptosis of pulmonary artery smooth muscle cells (PASMCs) are the basis for the development of pulmonary vascular remodeling, and it is the driving force for pulmonary arterial hypertension (PAH). 18ß-glycyrrhetinic acid (18ß-GA) is the main active substance extracted from Chinese herbal medicine licorice, with outstanding anti-inflammatory, anti-oxidation and anti-proliferative effects. Our team found in previous studies that 18ß-GA has protective effects on monocrotaline-induced PAH in rats. However, the anti-angiogenic effect of 18ß-GA on PAH remains unclear. Therefore, in order to further investigate whether the beneficial effects of 18ß-GA on PAH are related to its antiproliferative effect, we conducted experiments in vivo and in vitro. METHODS AND RESULTS: In vivo, 18ß-GA relieved mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricular hypertrophy index, improving pulmonary remodeling. In vitro, 18ß-GA significantly inhibited PDGF-BB-induced proliferation and DNA synthesis of HPASMCs, blocking the progression of G0/G1 to S phase of the cell cycle. Furthermore, after treatment with 18ß-GA, the expression of Rho A, ROCK1, ROCK2 was decreased and ROCK activity was inhibited in HPASMC. In addition, 18ß-GA also attenuated PDGF-induced changes in p27kip1, Bax and Bcl-2. CONCLUSIONS: In summary, these results indicate that 18ß-GA regulates the activity of RhoA-ROCK signaling pathway, inhibits the proliferation of HPASMCs, and has potential value in the treatment of PAH.


Assuntos
Ácido Glicirretínico/análogos & derivados , Hipertensão Pulmonar/patologia , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glicirretínico/farmacologia , Ácido Glicirretínico/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Masculino , Monocrotalina/toxicidade , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Substâncias Protetoras/uso terapêutico , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacos , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
3.
Anticancer Res ; 39(6): 3255-3264, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177176

RESUMO

BACKGROUND/AIM: Chemotherapy-induced cardiotoxicity may be observed during treatment or may cause severe cardiac failure as the main cause of death, even several years after therapy implementation. Herein, the aim was to establish the early diagnosis of cardiotoxicity through the periodic evaluation of the left ventricular (LV) and vascular remodeling parameters, in patients with acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: The study population included 35 patients diagnosed with ALL, evaluated before and 3 months after starting chemotherapy, measuring systolic and diastolic parameters of the LV and intima-media thickness (IMT), arterial stiffness aortic pulse wave velocity (PWVAo) and ankle-brachial index (ABI). RESULTS: After the first 2 cycles of chemotherapy, all patients experienced a drop in LV ejection fraction (LVEF) (p<0.001), and 12 patients suffered a decrease of LVEF<50%. The ABI (p<0.05) and the global longitudinal strain (GLS) (p<0.001) decreased, while IMT and PWVAo (p<0.001) increased, proving a subclinical deterioration of the LV function and vascular remodeling. CONCLUSION: Assessment of cardiovascular risk factors before chemotherapy initiation in ALL patients may be helpful for an early diagnosis of chemotherapy-induced cardiotoxicity, thus contributing to early treatment and a subsequent decrease of death caused by such cardiovascular complications.


Assuntos
Índice Tornozelo-Braço , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Cardiovasculares/diagnóstico , Ecocardiografia Doppler , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto , Cardiotoxicidade , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/fisiopatologia , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Valor Preditivo dos Testes , Fatores de Risco , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Remodelação Vascular/efeitos dos fármacos , Rigidez Vascular/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Adulto Jovem
4.
BMC Complement Altern Med ; 19(1): 127, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196042

RESUMO

BACKGROUND: Xin-Ji-Er-Kang (XJEK) is a Chinese herbal formula, which has been reported to exert effective protection against cardiovascular diseases, including hypertension and myocarditis. METHODS: Cultured human umbilical vascular endothelial cells (HUVECs) were treated with angiotensin II (Ang II) and different concentrations of aqueous layer extracts (AqE). Subsequently nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) expression levels were detected. In addition, fifty Kunming mice were randomized into control, Nω-nitro-L-arginine methyl ester (L-NAME), L-NAME+AqE, L-NAME+XJEK and L-NAME+fosinopril treatment groups. Following 8 weeks of treatment, the cardiac hemodynamic index was measured, relaxation of the aorta was examined and pathological changes were observed. Colorimetric analysis and enzyme linked immunosorbent assay (ELISA) were applied to determine the relevant indicators in plasma and cardiac tissues. RESULTS: The in vitro study results demonstrated that AqE could preserve endothelial function (NO, 21.05 ± 2.03 vs. 8.64 ± 0.59; eNOS, 1.08 ± 0.17 vs.0.73 ± 0.06). In addition, the in vivo results demonstrated that compared with the control group, treatment with AqE could enhance a high hemodynamic state (left ventricular systolic pressure, 116.76 ± 9.96 vs.114.5 ± 15.16), improve endothelial function (NO, 7.98 ± 9.64 vs. 1.66 ± 3.11; eNOS, 19.78 ± 3.18 vs.19.38 ± 3.85), suppress oxidative stress (OS) (superoxide dismutase, 178.17 ± 13.78 vs. 159.38 ± 18.86; malondialdehyde, 0.77 ± 0.13 vs.1.25 ± 0.36) and reverse cardiovascular remodeling. CONCLUSION: Polysaccharide from XJEK exerts protective effects against Ang II-induced injury in HUVECs and L-NAME-induced hypertension in mice and the underlying mechanism may be attributed to improving endothelial dysfunction, OS and the inflammation status in mice.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Remodelação Vascular/efeitos dos fármacos , Angiotensina II , Animais , Aorta/efeitos dos fármacos , Arginina/análogos & derivados , Arginina/sangue , Pressão Sanguínea/efeitos dos fármacos , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Malondialdeído/sangue , Camundongos , Miocárdio/metabolismo , NG-Nitroarginina Metil Éster , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Superóxido Dismutase/sangue
5.
Gen Physiol Biophys ; 38(4): 271-280, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31219429

RESUMO

The aim of this study was to investigate the effects of the Rho GDP dissociation inhibitor (RhoGDI) on TGFß1-mediated vascular adventitia myofibroblast transdifferentiation and on the inhibition of ROCK inhibitors. Myofibroblast transdifferentiation and vascular remodeling model were induced by TGFß1 in vitro and by balloon injury in vivo. H&E (Hematoxylin & Eosin) and PSR (Picrosirius Red) staining were used to observe vascular morphology while immunofluorescence, immunohistochemistry, and Western blotting were used to measure protein expression. Fasudil treatment reduced the expression of TGFß1, RhoGDI1, and RhoGDI2 in addition to vascular remodeling in the rat balloon injury model. TGFß1 induced the expression of α-SMA, TGFßRI, phospho-TGFßRI, RhoGDI1, RhoGDI2, and collagen secretion in human aortic adventitial fibroblasts (HAAFs). These effects were diminished after treatment with Y27632. Suppressing both RhoGDI1 and RhoGDI2 expression also blocked TGFß1-induced α-SMA expression and collagen secretion in HAAFs. Moreover, TGFßR inhibition blocked TGFß1-mediated collagen secretion and the expression of α-SMA, RhoGDI1, and RhoGDI2. These data suggested that ROCK inhibitors alleviate myofibroblast transdifferentiation and vascular remodeling by decreasing TGFß1-mediated expression of RhoGDI.


Assuntos
Transdiferenciação Celular/efeitos dos fármacos , Miofibroblastos/citologia , Miofibroblastos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Remodelação Vascular/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidores , Inibidores da Dissociação do Nucleotídeo Guanina rho-Específico/biossíntese , Animais , Humanos , Ratos
6.
Isr Med Assoc J ; 5(21): 345-352, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31140228

RESUMO

BACKGROUND: Angiogenesis is the outgrowth of new blood vessels from existing ones and is an early occurrence in inflamed joint tissue. It is governed by a tightly controlled balance of pro- and anti-angiogenic stimuli, which promote or inhibit generation and proliferation of new endothelial cells, vascular morphogenesis, and vessel remodeling. At the beginning, capillary formation is crucial in maintaining the supply of various nutrients as well as oxygen to the inflamed tissue. Local and systemic expression of angiogenic factors may indicate a constant remodeling of synovial vasculature. Redox signaling is closely related to angiogenesis and can alter angiogenic responses of synovial cells. In this review we discuss key issues about the endothelial pathology in inflammatory arthritis followed by a review of angiogenic processes and main angiogenic mediators. We discuss the hypoxia-vascular endothelial growth factor (VEGF)-Ang/Tie2 system and its related therapeutic implications in detail with further review of various mediator protein targets and intracellular regulatory pathway targets with their current and potential future role in preclinical or clinical setting whilst ameliorating inflammation.


Assuntos
Artrite Reumatoide , Neovascularização Patológica , Membrana Sinovial , Proteínas Angiogênicas/metabolismo , Anti-Inflamatórios/farmacologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Artrite Reumatoide/fisiopatologia , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/imunologia , Membrana Sinovial/irrigação sanguínea , Membrana Sinovial/imunologia , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/imunologia
7.
Vasc Endovascular Surg ; 53(5): 379-386, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30982448

RESUMO

INTRODUCTION: Oral statins reduce intimal hyperplasia (IH) after arterial injury by only ∼25%. Alternative drug delivery systems have gained attention as carriers for hydrophobic drugs. We studied the effects of simvastatin (free vs hyaluronic acid-tagged polysialic acid-polycaprolactone micelles) on vascular smooth muscle cell (VSMC) migration, VSMC proliferation and intimal hyperplasia. We hypothesized both free and micelle containing simvastatin would inhibit VSMC chemotaxis and proliferation, and local statin treatment would be more effective than oral in reducing IH in rats following carotid balloon injury. METHODS: VSMCs pretreated with free simvastatin (20 minutes or 20 hours) or simvastatin-loaded micelles underwent chemotaxis and proliferation to platelet-derived growth factor. Next, rats that underwent balloon injury of the common carotid artery received statin therapy-intraluminal simvastatin-loaded micelles prior to injury, periadventitial pluronic gel following injury, or combinations of gel, micelle, and oral simvastatin. After 14 days, morphometric analysis determined the -intimal to medial ratio. Findings were compared to controls receiving oral simvastatin or no statin therapy. Statistical analysis was by analysis of variance for the in vitro experiments and a factorial general linear model for the in vivo experiments. RESULTS: The simvastatin-loaded micelles and free simvastatin inhibited VSMC chemotaxis (54%-60%). IH was induced in all injured vessels. Simvastatin in pluronic gel or micelles reduced IH compared to untreated controls (0.208 ± 0.04 or 0.160 ± 0.03 vs 0.350 ± 0.03, respectively); however, neither gel nor simvastatin-loaded micelles were superior to oral statins (0.261 ± 0.03). Addition of oral statins or combining both local therapies did not provide additional benefit. Micelles were the single greatest contributing factor in IH attenuation. CONCLUSIONS: Intraluminally or topically delivered statins reduced IH. The efficacy of single-dose, locally delivered statin alone may lead to novel treatments to prevent IH. The different routes of administration may allow for treatment during endovascular procedures, without the need for systemic therapy.


Assuntos
Lesões das Artérias Carótidas/tratamento farmacológico , Artéria Carótida Primitiva/efeitos dos fármacos , Portadores de Fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Neointima , Polímeros/química , Sinvastatina/administração & dosagem , Túnica Íntima/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Administração Oral , Animais , Caproatos/química , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/fisiopatologia , Artéria Carótida Primitiva/metabolismo , Artéria Carótida Primitiva/patologia , Artéria Carótida Primitiva/fisiopatologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Composição de Medicamentos , Humanos , Ácido Hialurônico/química , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Lactonas/química , Micelas , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Ratos Sprague-Dawley , Ácidos Siálicos/química , Sinvastatina/química , Túnica Íntima/metabolismo , Túnica Íntima/patologia , Túnica Íntima/fisiopatologia
8.
Vascul Pharmacol ; 116: 45-50, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30946986

RESUMO

Since the first successful launch of the Veterans Administration(VA) cooperative studies in the late 1960s, the increasing access to blood pressure lowering medications has significantly contributed to improving longevity and quality of life in hypertensive patients. Since then, insights into the pathogenesis of hypertension have shown a mechanistic role for reactive oxygen species (ROS) in all phases of disease progression, suggesting the potential utility of antioxidant therapies to counteract symptoms and, at the same time, treat a fundamental mechanism of the disease. Despite these progresses, hypertension still remains the main contributor to the global incidence of cardiovascular disease and the leading cause of morbidity and mortality worldwide. We here briefly review and update the role of ROS and ROS-dependent metalloproteinase activation in the maladaptive remodeling of the vascular wall in hypertension. Such understanding should provide new Potential sites of action for antioxidant therapies as an integrated therapeutic approach to hypertension and its consequences.


Assuntos
Anti-Hipertensivos/uso terapêutico , Antioxidantes/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Rigidez Vascular/efeitos dos fármacos , Animais , Ativação Enzimática , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Metaloproteinases da Matriz/metabolismo
9.
Int J Mol Sci ; 20(6)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909527

RESUMO

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial proliferation and remodeling, resulting in a specific increase in right ventricle systolic pressure (RVSP) and, ultimately right ventricular failure. Recent studies have demonstrated that caffeic acid phenethyl ester (CAPE) exerts a protective role in NF-κB-mediated inflammatory diseases. However, the effect of CAPE on PAH remains to be elucidated. In this study, monocrotaline (MCT) was used to establish PAH in rats. Two weeks after the induction of PAH by MCT, CAPE was administrated by intraperitoneal injection once a day for two weeks. Pulmonary hemodynamic measurements and pulmonary artery morphological assessments were examined. Our results showed that administration of CAPE significantly suppressed MCT-induced vascular remodeling by decreasing the HIF-1α expression and PDGF-BB production, and improved in vivo RV systolic performance in rats. Furthermore, CAPE inhibits hypoxia- and PDGF-BB-induced HIF-1α expression by decreasing the activation of the AKT/ERK pathway, which results in the inhibition of human pulmonary artery smooth muscle cells (hPASMCs) proliferation and prevention of cells resistant to apoptosis. Overall, our data suggest that HIF-1α is regarded as an alternative target for CAPE in addition to NF-κB, and may represent a promising therapeutic agent for the treatment of PAH diseases.


Assuntos
Ácidos Cafeicos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Álcool Feniletílico/análogos & derivados , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Expressão Gênica , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Imuno-Histoquímica , Álcool Feniletílico/farmacologia , Fator de Crescimento Derivado de Plaquetas/genética , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos
10.
Nutrients ; 11(3)2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-30857304

RESUMO

Polyphenols present in some alcoholic beverages have been linked to beneficial effects in preventing cardiovascular diseases. Polyphenols found in beer with anti-proliferative and anti-cancer properties are appealing in the context of the quasi-malignant phenotype of pulmonary arterial hypertension (PAH). Our purpose was to evaluate if the chronic ingestion of a xanthohumol-fortified beer (FB) would be able to modulate the pathophysiology of experimental PAH. Male Wistar rats with monocrotaline (MCT)-induced PAH (60 mg/kg) were allowed to drink either xanthohumol-fortified beer (MCT + FB) or 5.2% ethanol (MCT + SHAM) for a period 4 weeks. At the end of the protocol, cardiopulmonary exercise testing and hemodynamic recordings were performed, followed by sample collection for further analysis. FB intake resulted in a significant attenuation of the pulmonary vascular remodeling in MCT + FB animals. This improvement was paralleled with the downregulation in expression of proteins responsible for proliferation (ERK1/2), cell viability (AKT), and apoptosis (BCL-XL). Moreover, MCT + FB animals presented improved right ventricle (RV) function and remodeling accompanied by VEGFR-2 pathway downregulation. The present study demonstrates that a regular consumption of xanthohumol through FB modulates major remodeling pathways activated in experimental PAH.


Assuntos
Cerveja/análise , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flavonoides/administração & dosagem , Hipertensão Pulmonar/induzido quimicamente , Propiofenonas/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Remodelação Vascular/efeitos dos fármacos , Animais , MAP Quinases Reguladas por Sinal Extracelular/genética , Flavonoides/química , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipertensão Pulmonar/patologia , Masculino , Monocrotalina/toxicidade , Propiofenonas/química , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Wistar
11.
Mol Med Rep ; 19(5): 3743-3755, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896818

RESUMO

Gap junctions (GJs) formed by connexins (Cxs) in T lymphocytes have been reported to have important roles in the T lymphocyte­driven inflammatory response and hypertension­mediated inflammation. Estrogen has a protective effect on cardiovascular diseases, including hypertension and it attenuates excessive inflammatory responses in certain autoimmune diseases. However, the mechanisms involved in regulating the pro­inflammatory response are complex and poorly understood. The current study investigated whether ß­estradiol suppresses hypertension and pro­inflammatory stimuli­mediated inflammatory responses by regulating Cxs and Cx­mediated GJs in peripheral blood lymphocytes. Male, 16­week­old spontaneously hypertensive rats (SHR) and Wistar­Kyoto rats (WKY) rats were randomly divided into the following three groups: WKY rats, vehicle (saline)­treated SHRs, and ß­estradiol (20 µg/kg/day)­treated SHRs. ß­estradiol was administered subcutaneously for 5 weeks. Hematoxylin and eosin staining was performed to evaluate target organ injury. Flow cytometry and ELISA were used to measure the populations of T lymphocyte subtypes in the peripheral blood, and expression of Cx40/Cx43 in T cell subtypes, and pro­inflammation cytokines levels, respectively. ELISA, a dye transfer technique, immunofluorescence and immunoblotting were used to analyze the effect of ß­estradiol on pro­inflammatory cytokine secretion, Cx­mediated GJs and the expression of Cxs in concanavalin A (Con A)­stimulated peripheral blood lymphocytes isolated from WKY rat. ß­estradiol significantly decreased blood pressure and inhibited hypertension­induced target organ injury in SHRs. Additionally, ß­estradiol treatment significantly improved the immune homeostasis of SHRs, as demonstrated by the decreased percentage of cluster of differentiation (CD)4+/CD8+ T­cell subset ratio, reduced serum levels of pro­inflammatory cytokines and increased the percentage of CD4+CD25+ T cells. ß­estradiol also markedly reduced the expression of Cx40/Cx43 in T lymphocytes from SHRs. In vitro, ß­estradiol significantly suppressed the production of pro­inflammatory cytokines, reduced communication via Cx­mediated gap junctions and decreased the expression of Cx40/Cx43 in Con A­stimulated lymphocytes. These results indicate that ß­estradiol attenuates inflammation and end organ damage in hypertension, which may be partially mediated via downregulated expression of Cxs and reduced function of Cx­mediated GJ.


Assuntos
Concanavalina A/efeitos adversos , Conexinas/metabolismo , Estradiol/farmacologia , Hipertensão/complicações , Inflamação/etiologia , Inflamação/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Conexina 43/genética , Conexina 43/metabolismo , Conexinas/genética , Citocinas/sangue , Citocinas/metabolismo , Junções Comunicantes/metabolismo , Expressão Gênica , Hipertensão/fisiopatologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Ratos , Remodelação Vascular/efeitos dos fármacos
12.
Oxid Med Cell Longev ; 2019: 5018410, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30805081

RESUMO

Proliferation and oxidative stress of vascular smooth muscle cells (VSMCs) contribute to vascular remodeling in hypertension and several major vascular diseases. B-cell lymphoma 6 (BCL6) functions as a transcriptional repressor. The present study is designed to determine the roles of BCL6 in VSMC proliferation and oxidative stress and underlying mechanism. Angiotensin (Ang) II was used to induce VSMC proliferation and oxidative stress in human VSMCs. Effects of BCL6 overexpression and knockdown were, respectively, investigated in Ang II-treated human VSMCs. Therapeutical effects of BCL6 overexpression on vascular remodeling, oxidative stress, and proliferation were determined in the aorta of spontaneously hypertensive rats (SHR). Ang II reduced BCL6 expression in human VSMCs. BCL6 overexpression attenuated while BCL6 knockdown enhanced the Ang II-induced upregulation of NADPH oxidase 4 (NOX4), production of reactive oxygen species (ROS), and proliferation of VSMCs. BCL6 expression was downregulated in SHR. BCL6 overexpression in SHR reduced NOX4 expression, ROS production, and proliferation of the aortic media of SHR. Moreover, BCL6 overexpression attenuated vascular remodeling and hypertension in SHR. However, BCL6 overexpression had no significant effects on NOX2 expression in human VSMCs or in SHR. We conclude that BCL6 attenuates proliferation and oxidative stress of VSMCs in hypertension.


Assuntos
Hipertensão/metabolismo , Hipertensão/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Angiotensina II/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aorta/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Hipertensão/fisiopatologia , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Remodelação Vascular/efeitos dos fármacos
13.
Eur J Pharmacol ; 850: 97-108, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30753867

RESUMO

Accumulating evidence suggests that epidermal growth factor receptor (EGFR) plays a role in the progression of pulmonary arterial hypertension (PAH). Clinically-approved epidermal growth factor inhibitors such as gefitinib, erlotinib, and lapatinib have been explored for PAH. However, None of them were able to attenuate PAH. So, we explored the role of dacomitinib, a new pan-EGFR inhibitor, in PAH. Adult male Sprague-Dawley rats were used to study hypoxia- or monocrotaline-induced right ventricular remodeling as well as systolic function and hemodynamics using echocardiography and a pressure-volume admittance catheter. Morphometric analyses of lung vasculature and pressure-volume vessels were performed. Immunohistochemical staining, flow cytometry, and viability, as well as scratch-wound, and Boyden chamber migration assays were used to identify the roles of dacomitinib in pulmonary artery smooth muscle cells (PASMCs). The results revealed that dacomitinib has a significant inhibitory effect on the thickening of the media, adventitial collagen increased. Dacomitinib also has a significant role in attenuating pulmonary artery pressure and right ventricular hypertrophy. Additionally, dacomitinib inhibits hypoxia-induced proliferation, migration, autophagy and cell cycle progression through PI3K-AKT-mTOR signaling in PASMCs. Our study indicates that dacomitinib inhibited hypoxia-induced cell cycle progression, proliferation, migration, and autophagy of PASMCs, thereby attenuating pulmonary vascular remodeling and development of PAH via the PI3K-AKT-mTOR signaling pathway. Overall, dacomitinib may serve as new potential therapeutic for the treatment of PAH.


Assuntos
Receptores ErbB/antagonistas & inibidores , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/patologia , Pulmão/irrigação sanguínea , Quinazolinonas/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinonas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
14.
Eur J Pharmacol ; 850: 126-134, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30753868

RESUMO

Studies on the role of Rho-associated protein kinase (ROCK) in experimental pulmonary artery hypertension (PAH) relies mainly on the use of pharmacological inhibitors. However, interpreting these data is hampered by the lack of specificity of commonly utilized inhibitors. To fill this gap, we have selected and characterized a novel ROCK inhibitor, Compound 3, previously described in a patent. Inhibitory potency of Compound 3 against enzymatic activity of ROCK-1 and 2 (IC50 = 10 ±â€¯3.1 and 7.8 ±â€¯0.5 nM, respectively) was accompanied by a strong vasodilating effect in phenylephrine pre-contracted isolated rat pulmonary artery rings (IC50 = 51.7 ±â€¯9.1 nM) as well as in aortic rings (IC50 = 45.5 ±â€¯1.1 nM). Compound 3 showed a remarkable selectivity towards ROCK 1 and 2 when tested against a large panel (>400) of human kinases. A partial explanation for its selectivity is provided from docking simulations within ROCK-1. Pharmacokinetic studies showed that Compound 3 is suitable for a twice daily administration without significant accumulation upon repeated dosing. In rats with monocrotaline (MCT)-induced pulmonary hypertension, therapy with Compound 3, (1 and 3 mg/kg, s.c., b.i.d.), started 14 days after induction of the disease, attenuated right ventricle systolic pressure (RVSP) increase. Morphometric histological analysis showed that Compound 3, at both doses, counteracted MCT-induced medial thickening of lung distal arterioles with an effect comparable to macitentan (10 mg/kg, p.o., q.d.). Compound 3 is a potent and highly selective ROCK inhibitor that ameliorates hemodynamic parameters and counteracts pulmonary vascular remodeling in experimental PAH.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aorta/fisiopatologia , Antagonistas dos Receptores de Endotelina/farmacologia , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Ratos , Distribuição Tecidual , Remodelação Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Quinases Associadas a rho/química , Quinases Associadas a rho/metabolismo
15.
Biomed Pharmacother ; 112: 108651, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784931

RESUMO

The protective role of alkaloids from Nelumbinis Plumula (AFNP) on the aorta during hypertension is not yet fully understood. We hypothesize that AFNP exerts protective effects against Ang II-induced hypertension by mediating RhoA/ROCK pathway and phenotypic switching during hypertension. In the present study, we evaluated the effect of AFNP on angiotensin II (Ang II)-induced actin cytoskeleton reorganization and aorta remodeling, as well as the involvement of RhoA/Rho-associated coiled kinase (ROCK) pathway in protecting against hypertension. We used rat aortic tissues to investigate the vasodilatation effect of AFNP on Ang II-induced constriction. AFNP was shown to significantly relax the endothelium-intact arteries induced by Ang II. We further investigated the vasodilation effect of AFNP in endothelium denuded arteries, which showed that the action of AFNP was endothelial independent. Male SHR rats were treated with saline or AFNP and morphological changes were examined following 8 weeks. AFNP treatment normalized the effects of hypertension in SHRs. HE staining showed that AFNP treatment improved the tunica media and wall thickness and ratio of MT/LD and MA/LA. Western blotting showed that AFNP treatment markedly decreased the Ang II-induced expression of collagen I and increased α-SMA in aorta. Furthermore, MTT assay showed that AFNP inhibited the proliferation of Ang II treated VSMCs in a concentration-dependent manner. AFNP treatment also ameliorated F-actin cytoskeleton remodeling in Ang II treated VSMCs, as visualized under fluorescence microscopy. Western blot analysis showed that RhoA transposition and ROCK activation and phosphorylation of MYPT1 was increased following Ang II treatment but were inhibited by AFNP treatment, showing that the cardio-protective effect of AFNP is likely mediated by the RhoA/ROCK signaling pathway. The anti-hypertension and aortic protection effects of AFNP are due to non-endothelial dependent inhibition of the VSMC cytoskeleton remodeling and regulation of RhoA/ROCK pathway.


Assuntos
Alcaloides/farmacologia , Aorta Torácica/efeitos dos fármacos , Nelumbo , Remodelação Vascular/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/fisiologia , Quinases Associadas a rho/fisiologia , Alcaloides/isolamento & purificação , Animais , Aorta Torácica/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Sementes , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Remodelação Vascular/fisiologia
16.
Life Sci ; 219: 82-89, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30605649

RESUMO

AIM: Pulmonary hypertension due to left heart failure (PH-LHF) is the most common cause of pulmonary hypertension. However, therapies for PH-LHF are lacking. Therefore, we investigated the effects and potential mechanism of dehydroepiandrosterone (DHEA) treatment in an experimental model of PH-LHF. MAIN METHOD: PH-LHF was induced in rats via ascending aortic banding. The rats then received daily DHEA from Day 1 to Day 63 for the prevention protocol or from Day 49 to Day 63 for the reversal protocol. Other ascending aortic banding rats were left untreated to allow development of PH and right ventricular (RV) failure. Sham ascending aortic banding rats served as controls. KEY FINDING: Significant increases in mean pulmonary arterial pressure (mPAP) and right ventricular end-diastolic diameter (RVEDD) were observed in the PH-LHF group. Therapy with DHEA prevented LHF-induced PH and RV failure by preserving mPAP and preventing RV hypertrophy and pulmonary artery remodeling. In preexisting severe PH, DHEA attenuated most lung and RV abnormalities. The beneficial effects of DHEA in PH-LHF seem to result from depression of the STAT3 signaling pathway in the lung. SIGNIFICANT: DHEA not only prevents the development of PH-LHF and RV failure but also rescues severe preexisting PH-LHF.


Assuntos
Desidroepiandrosterona/uso terapêutico , Insuficiência Cardíaca/complicações , Hipertensão Pulmonar/etiologia , Artéria Pulmonar/fisiopatologia , Remodelação Vascular/efeitos dos fármacos , Remodelação Ventricular/fisiologia , Animais , Western Blotting , Modelos Animais de Doenças , Ecocardiografia , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Masculino , Artéria Pulmonar/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
17.
Life Sci ; 219: 303-310, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30677425

RESUMO

AIMS: Vascular adventitial fibroblasts (AFs) in the vascular remodeling during atherosclerosis are increasing arousing attention. Acid sphingomyelinase (ASM) is a soluble glycoprotein which is involved in the development and progression of atherosclerosis. However, it remains unknown if ASM is expressed in vascular AFs and regulates vascular adventitial remodeling and underlying mechanisms. MAIN METHODS AND KEY FINDINGS: ASM downregulation with gene silencing was used in the rat AFs treated with angiotensin (Ang) II, which is universally demonstrated to induce vascular adventitia remodeling. It was showed that ASM was indeed expressed in vascular AFs and ASM downregulation resulted in a significant decrease in the protein level of PCNA and collagen I and cell migration under Ang II stimulation. Such improvement of adventitial remodeling was not further augmented by Ang-(1-7), which is deemed as an endogenous Ang II blocker. We further found that ASM downregulation blocked the Nox2-dependent superoxide (O2-) generation, which regulated vascular remodeling in AFs under Ang II. ASM siRNA decreased the aggregation of membrane rafts (MRs) and the consequent recruiting of ceramide and Nox2 in MRs. SIGNIFICANCE: In conclusion, these results suggested that ASM downregulation could improve vascular adventitial remodeling which was attributed to inhibiting MRs/Nox2 redox signaling pathway in AFs. Thus, these data supported the idea that ASM is a potential therapeutic target for diabetic vascular complication.


Assuntos
Angiotensina II/farmacologia , Microdomínios da Membrana/metabolismo , NADPH Oxidase 2/metabolismo , Transdução de Sinais , Esfingomielina Fosfodiesterase/fisiologia , Remodelação Vascular/efeitos dos fármacos , Túnica Adventícia/efeitos dos fármacos , Túnica Adventícia/metabolismo , Túnica Adventícia/fisiologia , Animais , Western Blotting , Inativação Gênica , Imunoprecipitação , Masculino , Microscopia Confocal , NADPH Oxidase 2/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Esfingomielina Fosfodiesterase/metabolismo , Remodelação Vascular/fisiologia
18.
Eur J Pharmacol ; 847: 32-41, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30659826

RESUMO

Magnesium lithospermate B (MLB) shows multiple biological activities including anti-oxidation and anti-proliferation in various diseases. However, the function of MLB in pulmonary arterial hypertension (PAH) is still unknown. This study aims to investigate the effect of MLB on hypoxia-induced phenotypic transformation of pulmonary arterial smooth muscle cells (PASMCs) and the underlying mechanisms. SD rats (or PASMCs) were exposed to 10% O2 for 3 weeks (or 3% O2 for 48 h) along with MLB or NADPH oxidase (NOX) inhibitor intervention. The effects of MLB on hemodynamics, pulmonary vascular remodeling and phenotypic transformation of PASMCs were observed first. Then, its effects on the protein levels of NOX (NOX2 and NOX4), ERK and p-ERK were examined. The results showed that MLB prevented the elevation in right ventricular systolic pressure and the increase in ratio of wall thickness to vessel external diameter of pulmonary arteries in PAH rats, and attenuated phenotypic transformation of PASMCs (decrease in α-smooth muscle actin while increase in osteopontin), accompanied by downregulation of NOX (NOX2 and NOX4) protein levels, decrease of ROS and H2O2 production, and suppression of the phosphorylation of ERK. NOX inhibitor (VAS2870) achieved similar results to that of MLB did in the hypoxia-treated PASMCs. Based on the observations, we conclude that MLB is able to prevent phenotypic transformation of pulmonary arteries in hypoxic PAH rats through suppression of NOX/ROS/ERK pathway, and MLB might have the potentials in PAH therapy.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/tratamento farmacológico , Magnésio/farmacologia , NADPH Oxidases/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Animais , Linhagem Celular , Peróxido de Hidrogênio/metabolismo , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Fosforilação/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos
19.
Hypertension ; 73(3): 703-711, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30636546

RESUMO

Pulmonary arterial hypertension is a fatal lung disease caused by the progressive remodeling of small pulmonary arteries (PAs). Sildenafil can prevent the remodeling of PAs, but conventional sildenafil formulations have shown limited treatment efficacy for their poor accumulation in PAs. Here, glucuronic acid (GlcA)-modified liposomes (GlcA-Lips) were developed to improve the delivery of sildenafil to aberrant over-proliferative PA smooth muscle cells via targeting the GLUT-1 (glucose transport-1), and, therefore, inhibiting the remodeling of PAs in a monocrotaline-induced PA hypertension model. GlcA-Lips encapsulating sildenafil (GlcA-sildenafil-Lips) had a size of 90 nm and a pH-sensitive drug release pattern. Immunostaining assay indicated the overexpression of GLUT-1 in PA smooth muscle cells. Cellular uptake studies showed a 1-fold increase of GlcA-Lips uptake by PA smooth muscle cells and pharmacokinetics and biodistribution experiments indicated longer blood circulation time of GlcA-Lips and increased ability to target PAs by 1-fold after 8 hours administration. Two-week treatment indicated GlcA-sildenafil-Lips significantly inhibited the remodeling of PAs, with a 32% reduction in the PA pressure, a 41% decrease in the medial thickening, and a 44% reduction of the right ventricle cardiomyocyte hypertrophy, and improved survival rate. Immunohistochemical analysis showed enhanced expression of caspase-3, after administration of GlcA-sildenafil-Lips, and reduced expression of P-ERK1/2 (phosphorylated ERK1/2) and HK-2 (hexokinase-2), and increased level of eNOS (endothelial nitric oxide synthase) and cyclic GMP (cGMP). In conclusion, targeted delivery of sildenafil to PA smooth muscle cells with GlcA-Lips could effectively inhibit the remodeling of PAs in the monocrotaline-induced PA hypertension.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Artéria Pulmonar/fisiopatologia , Citrato de Sildenafila/administração & dosagem , Remodelação Vascular/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Hipertensão Pulmonar/fisiopatologia , Imuno-Histoquímica , Lipossomos , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Citrato de Sildenafila/farmacocinética , Distribuição Tecidual , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacocinética , Função Ventricular Direita/fisiologia
20.
J Pharmacol Exp Ther ; 368(3): 514-523, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30606762

RESUMO

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor γ (PPARγ) agonists that represent an effective class of insulin-sensitizing agents; however, clinical use is associated with weight gain and peripheral edema. To elucidate the role of PPARγ expression in endothelial cells (ECs) in these side effects, EC-targeted PPARγ knockout (Pparg ΔEC) mice were placed on a high-fat diet to promote PPARγ agonist-induced plasma volume expansion, and then treated with the TZD rosiglitazone. Compared with Pparg-floxed wild-type control (Pparg f/f) mice, Pparg ΔEC treated with rosiglitazone are resistant to an increase in extracellular fluid, water content in epididymal and inguinal white adipose tissue, and plasma volume expansion. Interestingly, histologic assessment confirmed significant rosiglitazone-mediated capillary dilation within white adipose tissue of Pparg f/f mice, but not Pparg ΔEC mice. Analysis of ECs isolated from untreated mice in both strains suggested the involvement of changes in endothelial junction formation. Specifically, compared with cells from Pparg f/f mice, Pparg ΔEC cells had a 15-fold increase in focal adhesion kinase, critically important in EC focal adhesions, and >3-fold significant increase in vascular endothelial cadherin, the main component of focal adhesions. Together, these results indicate that rosiglitazone has direct effects on the endothelium via PPARγ activation and point toward a critical role for PPARγ in ECs during rosiglitazone-mediated plasma volume expansion.


Assuntos
Tecido Adiposo/metabolismo , Células Endoteliais/metabolismo , Hipoglicemiantes/farmacologia , PPAR gama/deficiência , Rosiglitazona/farmacologia , Remodelação Vascular/fisiologia , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/efeitos dos fármacos , Animais , Células Endoteliais/efeitos dos fármacos , Deleção de Genes , Masculino , Camundongos , Camundongos Transgênicos , PPAR gama/genética , Volume Plasmático/efeitos dos fármacos , Volume Plasmático/fisiologia , Remodelação Vascular/efeitos dos fármacos
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