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1.
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
2.
PLoS One ; 11(7): e0157171, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27388289

RESUMO

BACKGROUND: Pulmonary hypertension due to left heart disease (PH-LHD) is one of the most common forms of PH, termed group 2 PH. Atorvastatin exerts beneficial effects on the structural remodeling of the lung in ischemic heart failure. However, few studies have investigated the effects of atorvastatin on PH due to left heart failure induced by overload. METHODS: Group 2 PH was induced in animals by aortic banding. Rats (n = 20) were randomly divided into four groups: a control group (C), an aortic banding group (AOB63), an atorvastatin prevention group (AOB63/ATOR63) and an atorvastatin reversal group (AOB63/ATOR50-63). Atorvastatin was administered for 63 days after banding to the rats in the AOB63/ATOR63 group and from days 50 to 63 to the rats in the AOB63/ATOR50-63 group. RESULTS: Compared with the controls, significant increases in the mean pulmonary arterial pressure, pulmonary arteriolar medial thickening, biventricular cardiac hypertrophy, wet and dry weights of the right middle lung, percentage of PCNA-positive vascular smooth muscle cells, inflammatory infiltration and expression of RhoA and Rho-kinase II were observed in the AOB63 group, and these changes concomitant with significant decreases in the percentage of TUNEL-positive vascular smooth muscle cells. Treatment of the rats in the AOB63/ATOR63 group with atorvastatin at a dose of 10 mg/kg/day significantly decreased the mean pulmonary arterial pressure, right ventricular hypertrophy, pulmonary arteriolar medial thickness, inflammatory infiltration, percentage of PCNA-positive cells and pulmonary expression of RhoA and Rho-kinase II and significantly augmented the percentage of TUNEL-positive cells compared with the AOB63 group. However, only a trend of improvement in pulmonary vascular remodeling was detected in the AOB63/ATOR50-63 group. CONCLUSIONS: Atorvastatin prevents pulmonary vascular remodeling in the PH-LHD model by down-regulating the expression of RhoA/Rho kinase, by inhibiting the proliferation and increasing the apoptosis of pulmonary arterial smooth muscle cells, and by attenuating the inflammation of pulmonary arteries.


Assuntos
Atorvastatina/uso terapêutico , Cardiopatias/tratamento farmacológico , Hipertensão Pulmonar/tratamento farmacológico , Animais , Aorta/efeitos dos fármacos , Apoptose , Arteríolas/metabolismo , Proliferação de Células , Cardiopatias/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipertensão Pulmonar/fisiopatologia , Inflamação , Pulmão/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/fisiopatologia , Neutrófilos/metabolismo , Ratos , Ratos Sprague-Dawley
3.
Zhonghua Xin Xue Guan Bing Za Zhi ; 38(7): 638-43, 2010 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-21055290

RESUMO

OBJECTIVE: To observe the effects of mutant hypoxia-inducible factor-1α (HIF-1α) adenovirus (Adeno-HIF-1α-Ala402-Ala564) on cardiomyocytes (CMCs) differentiation from the mesenchymal stem cells (MSCs) co-cultured with CMCs. METHODS: Following groups were studied: HIF-1α group (MSCs + CMCs + Ad-HIF-1α), LacZ group (MSCs + CMCs + Ad-LacZ), Sham group (MSCs + CMCs + PBS) and MSC + HIF-1α Group (MSCs + Ad-HIF-1α). MSCs were co-cultured with myocardial cells in proportion of MSCs:CMCs 1:2, after 24 hours, cells were infect with virus (MOI = 100) or treated with PBS, cardiac troponin (cTnT) expression in MSCs was detected 7 days post infection by immunochemical analysis, mRNA expression of HIF-1α, TGF-ß(1), Smad4, NKx2.5, GATA-4 was also detected by RT-PCR. RESULTS: HIF-1α increased MSCs differentiation to myocardial cells (differentiation rate 32.68% ± 6.52% vs. 8.28% ± 0.09% in the LacZ group and 10.25% ± 2.20% in the Sham group and 0.32% ± 0.05% in the MSC group (all P < 0.05 vs. HIF-1α group). mRNA expression of HIF, TGF-ß(1), Smad4, NKx2.5 and GATA-4 was also significantly upregulated in HIF-1α group all P < 0.05 vs. Sham group). CONCLUSION: HIF-1α promoted MSCs, co-cultured with myocardial cells, differentiating to cardiomyocytes via upregulating TGF-ß(1)/Smad4 signaling pathway.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células-Tronco Mesenquimais/efeitos dos fármacos , Miócitos Cardíacos/citologia , Adenoviridae/genética , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Vetores Genéticos , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteína Smad4/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
4.
Am J Hypertens ; 22(6): 680-6, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19300423

RESUMO

BACKGROUND: Conjugated linoleic acid (CLA) refers to a group of positional and geometrical conjugated dienoic isomers of linoleic acid. Our aim was to investigate the effect of 8-week dietary CLA supplementation on blood pressure, concentrations of plasma adiponecin, leptin, and as well as angiotensin-converting enzyme (ACE) activity in obese hypertensive subjects. METHODS: Eighty obese individuals with stage 1 uncontrolled essential hypertension were randomized in a double-blind, placebo-controlled trial. Participants were randomized to a daily dose of 4.5 g/day CLA (nine 0.5-g capsules; a 50:50 isomer blend of c 9,t 11 and t 10,c 12 CLA) with 37.5 mg/day ramipril (group 1) or placebo with 37.5 mg/day ramipril (group 2) for 8 weeks. Baseline and endpoint systolic BP, diastolic BP, and concentrations of plasma adiponecin, leptin, angiotensinogen, and ACE activity were measured. RESULTS: Treatment with CLA significantly enhanced the reduction effect of ramipril on systolic BP and diastolic BP (P < 0.05). It also increased plasma adiponectin concentration (P < 0.05) and decreased plasma concentrations of leptin and angiotensinogen (P < 0.05); however, significant change was not observed in ACE activity. CONCLUSIONS: An 8-week long supplementation of CLA enhanced the effect of ramipril on blood pressure reduction in treated obese hypertensive patients. The antihypertensive effect of CLA might be related to the changed secretion of hypertensive adipocytokines in plasma.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Suplementos Nutricionais , Hipertensão/tratamento farmacológico , Ácidos Linoleicos Conjugados/uso terapêutico , Obesidade/complicações , Ramipril/uso terapêutico , Adiponectina/sangue , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Angiotensinogênio/sangue , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Sinergismo Farmacológico , Feminino , Seguimentos , Humanos , Hipertensão/epidemiologia , Hipertensão/etiologia , Leptina/sangue , Ácidos Linoleicos Conjugados/administração & dosagem , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/epidemiologia , Ramipril/administração & dosagem , Resultado do Tratamento
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