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1.
ESC Heart Fail ; 9(5): 3407-3417, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35841124

RESUMO

AIMS: Orchestrating the transition from reversible medial hypertrophy to irreversible plexiform lesions is crucial for pulmonary arterial hypertension related to congenital heart disease (CHD-PAH). Transgelin is an actin-binding protein that modulates pulmonary arterial smooth muscle cell (PASMC) dysfunction. In this study, we aimed to probe the molecular mechanism and biological function of transgelin in the pathogenesis of CHD-PAH. METHODS AND RESULTS: Transgelin expression was detected in lung tissues from both CHD-PAH patients and monocrotaline (MCT)-plus aortocaval (AV)-induced PAH rats by immunohistochemistry. In vitro, the effects of transgelin on the proliferation, migration, and apoptosis of human PASMCs (HPASMCs) were evaluated by the cell count and EdU assays, transwell migration assay, and TUNEL assay, respectively. And the effect of transgelin on the expression of HPASMC phenotype markers was assessed by the immunoblotting assay. (i) Compared with the normal control group (n = 12), transgelin expression was significantly overexpressed in the pulmonary arterioles of the reversible (n = 15) and irreversible CHD-PAH group (n = 4) (reversible group vs. control group: 18.2 ± 5.1 vs. 13.6 ± 2.6%, P < 0.05; irreversible group vs. control group: 29.9 ± 4.7 vs. 13.6 ± 2.6%, P < 0.001; irreversible group vs. reversible group: 29.9 ± 4.7 vs. 18.2 ± 5.1, P < 0.001). This result was further confirmed in MCT-AV-induced PAH rats. Besides, the transgelin expression level was positively correlated with the pathological grading of pulmonary arteries in CHD-PAH patients (r = 0.48, P = 0.03, n = 19). (ii) Compared with the normal control group (n = 12), TGF-ß1 expression was notably overexpressed in the pulmonary arterioles of the reversible (n = 15) and irreversible CHD-PAH group (n = 4) (reversible group vs. control group: 14.8 ± 4.4 vs. 6.0 ± 2.5%, P < 0.001; irreversible group vs. control group: 20.1 ± 4.4 vs. 6.0 ± 2.5%, P < 0.001; irreversible group vs. reversible group: 20.1 ± 4.4 vs. 14.8 ± 4.4, P < 0.01). The progression-dependent correlation between TGF-ß1 and transgelin was demonstrated in CHD-PAH patients (r = 0.48, P = 0.04, n = 19) and MCT-AV-induced PAH rats, which was further confirmed at sub-cellular levels. (iii) Knockdown of transgelin diminished proliferation, migration, apoptosis resistance, and phenotypic transformation of HPASMCs through repressing the TGF-ß1 signalling pathway. On the contrary, transgelin overexpression resulted in the opposite effects. CONCLUSIONS: These results indicate that transgelin may be an indicator of CHD-PAH development via boosting HPASMC dysfunction through positive regulation of the TGF-ß1 signalling pathway, as well as a potential therapeutic target for the treatment of CHD-PAH.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Animais , Humanos , Ratos , Proliferação de Células/genética , Hipertensão Pulmonar/etiologia , Proteínas dos Microfilamentos/metabolismo , Monocrotalina/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Hipertensão Arterial Pulmonar/etiologia , Artéria Pulmonar , Fator de Crescimento Transformador beta1/metabolismo
2.
J Cell Physiol ; 236(9): 6297-6311, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33507567

RESUMO

Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease (CHD). Deubiquitinase cylindromatosis (CYLD) has been reported to significantly aggravate vascular smooth muscle cell (VSMC) phenotypic transformation, proliferation, and migration. Here, we aimed to further investigate its roles and underlying mechanisms in the CHD-PAH development. The expression of CYLD in the lung tissues from CHD-PAH patients and monocrotaline (MCT) plus aortocaval (AV)-induced PAH rats, pulmonary artery smooth muscle cells (PASMCs) from MCT-AV-induced PAH rats, and human PASMCs (HPASMCs) was evaluated. After infection with CYLD siRNA or pcNDA3.1-CYLD, the proliferation, migration, and apoptosis of HPASMCs were measured using an EdU assay, transwell and scratch wound healing assays, and flow cytometric assay, respectively. An adeno-associated virus (AAV) vector encoding CYLD was used to suppress CYLD expression by being intratracheally instilled in rats 7 days before MCT-AV treatment. The results showed that CYLD was increased in the lung tissues from CHD-PAH patients and MCT-AV-induced PAH rats, and in PASMCs from MCT-AV-induced PAH rats. The contractile-type HPASMCs expressed low levels of CYLD, while the proliferative synthetic-type HPASMCs expressed high levels of CYLD. In addition, CYLD could mediate HPASMC dysfunction, which regulated HPASMC phenotypic transformation and proliferation via the modulation of p38 and ERK activation, while CYLD regulated HPASMC migration via the modulation of p38 activation. In vivo results demonstrated that the local suppression of CYLD expression could attenuate the increased levels of PAH and its associated pulmonary vascular remodeling in MCT-AV-induced PAH rats. Collectively, these results indicated that CYLD might be a potential novel therapeutic target for the prevention of PAH and pulmonary vascular remodeling in CHD-PAH through the modulation of HPASMC dysfunction.


Assuntos
Enzima Desubiquitinante CYLD/metabolismo , Cardiopatias Congênitas/complicações , Miócitos de Músculo Liso/patologia , Hipertensão Arterial Pulmonar/complicações , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/patologia , Adolescente , Adulto , Idoso , Animais , Apoptose , Biomarcadores/metabolismo , Movimento Celular , Proliferação de Células , Criança , Pré-Escolar , Feminino , Cardiopatias Congênitas/fisiopatologia , Hemodinâmica , Humanos , Pulmão/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Pessoa de Meia-Idade , Monocrotalina , NF-kappa B/metabolismo , Fenótipo , Ratos Sprague-Dawley , Soro , Ubiquitina Tiolesterase/metabolismo , Remodelação Vascular , Adulto Jovem
3.
J Mol Cell Cardiol ; 149: 41-53, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32950539

RESUMO

OBJECTIVE: Reportedly, nestin was re-expressed in proliferative synthetic-type pulmonary artery smooth muscle cells (PASMCs) and obligatory for PASMC proliferation in pulmonary arterial hypertension (PAH). Accordingly, nestin is increased in pulmonary vascular lesions of congenital heart disease (CHD)-associated PAH patients. We tested the hypothesis whether nestin was re-expressed in proliferative synthetic-type PASMCs and associated with pulmonary vascular remodeling in CHD-PAH. MATERIALS AND METHODS: Nestin expression was tested using lung tissues from CHD-PAH patients and monocrotaline (MCT) plus aortocaval (AV) shunt-induced PAH rats, human PASMCs (HPASMCs), and pulmonary artery endothelial cells (PAECs) and PASMCs from MCT-AV-induced PAH rats. The role and possible mechanism of nestin on HPASMC proliferation, apoptosis, cell cycle and migration were investigated by assays of CCK-8, EdU, TUNEL, flow cytometry, transwell chamber and immunoblotting assays. RESULTS: Nestin was solely expressed in proliferative synthetic-type PASMCs, but rarely detected in PAECs. Nestin was barely detected in normal pulmonary arterioles and occlusive pulmonary vascular lesions. Its expression was robustly increased in developing pulmonary vasculature, but returned to normal levels at the late stage of pulmonary vascular remodeling in lung tissues from CHD-PAH patients and MCT-AV-induced PAH rats. Besides, nestin peaks were consistent with the histological features in lung tissues of MCT-AV-induced PAH rats. Moreover, nestin overexpression effectively promoted HPASMC phenotypic transformation, proliferation, apoptosis resistance and migration via enhancing Wnt/ß-catenin activation. CONCLUSIONS: These data indicated that nestin was re-expressed in proliferative synthetic-type PASMCs and might represent a potential marker of pulmonary vascular remodeling in CHD-PAH.


Assuntos
Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/fisiopatologia , Pulmão/fisiopatologia , Nestina/metabolismo , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Remodelação Vascular , Adolescente , Adulto , Idoso , Animais , Biomarcadores/metabolismo , Criança , Pré-Escolar , Células Endoteliais/metabolismo , Feminino , Cardiopatias Congênitas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Monocrotalina , Miócitos de Músculo Liso/metabolismo , Fenótipo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Hipertensão Arterial Pulmonar/complicações , Artéria Pulmonar/patologia , Ratos Sprague-Dawley , Fatores de Tempo , Via de Sinalização Wnt , Adulto Jovem
4.
Arterioscler Thromb Vasc Biol ; 39(4): 704-718, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30816802

RESUMO

Objective- Pulmonary arterial hypertension is characterized by progressive pulmonary vascular remodeling and persistently elevated mean pulmonary artery pressures and pulmonary vascular resistance. We aimed to investigate whether transthoracic pulmonary artery denervation (TPADN) attenuated pulmonary artery (PA) remodeling, improved right ventricular (RV) function, and affected underlying mechanisms. We also explored the distributions of sympathetic nerves (SNs) around human PAs for clinical translation. Approach and Results- We identified numerous SNs in adipose and connective tissues around the main PA trunks and bifurcations in male Sprague Dawley rats, which were verified in samples from human heart transplant patients. Pulmonary arterial hypertensive rats were randomized into TPADN and sham groups. In the TPADN group, SNs around the PA trunk and bifurcation were completely and accurately removed under direct visualization. The sham group underwent thoracotomy. Hemodynamics, RV function, and pathological changes in PA and RV tissues were measured via right heart catheterization, cardiac magnetic resonance imaging, and pathological staining, respectively. Compared with the sham group, the TPADN group had lower mean pulmonary arterial pressures, less PA and RV remodeling, and improved RV function. Furthermore, TPADN inhibited neurohormonal overactivation of the sympathetic nervous system and renin-angiotensin-aldosterone system and regulated abnormal expressions and signaling of neurohormone receptors in local tissues. Conclusions- There are numerous SNs around the rat and human main PA trunks and bifurcations. TPADN completely and accurately removed the main SNs around PAs and attenuated pulmonary arterial hypertensive progression by inhibiting excessive activation of the sympathetic nervous system and renin-angiotensin-aldosterone system neurohormone-receptor axes.


Assuntos
Hipertensão Arterial Pulmonar/cirurgia , Simpatectomia/métodos , Adolescente , Aldosterona/fisiologia , Animais , Pré-Escolar , Citocinas/sangue , Progressão da Doença , Feminino , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipertrofia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Monocrotalina/toxicidade , Neurotransmissores/fisiologia , Estresse Oxidativo , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/inervação , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores de Neurotransmissores/biossíntese , Receptores de Neurotransmissores/genética , Receptores de Neurotransmissores/fisiologia , Sistema Renina-Angiotensina/fisiologia , Sistema Nervoso Simpático/anatomia & histologia
5.
Hypertens Res ; 28(3): 249-54, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16097369

RESUMO

An increase in reactive oxygen species has been shown to play a role in perpetuating hypertension and cerebral injury in stroke-prone spontaneously hypertensive rats (SHRsp). Lipid peroxidation in the cerebral cortex is much more intense in SHRsp after establishment of severe hypertension as compared to that in normotensive Wistar-Kyoto rats (WKY). Cortical neurons from SHRsp are more vulnerable to hypoxia and hyponutritional conditions. We sought to investigate whether long-term administration of seleno-glutathione peroxidase mimic ebselen (PZ51) would have a protective effect on cortical neurons in SHRsp, and, if so, the possible mechanisms of this effect. Twenty-two 8-week-old SHRsp were randomized into a PZ51 group and control group. Age-matched WKY were used as normal controls. We examined the levels of malonaldehyde (MDA) and nitric oxide (NO) in the cerebral cortex (CC) homogenate, detected the three isoforms of nitric oxide synthase (NOS) by Western blotting, and examined cortical neurons by transmission electron microscopy. The results showed that PZ51 treatment significantly decreased both MDA and NO in the CC, inhibited inducible nitric oxide synthase (iNOS) protein expression, and alleviated the damage to cortical neurons compared to the findings for the control group. In conclusion, the present study showed that PZ51 administration suppressed lipid peroxidation and inhibited iNOS protein expression in CC homogenate, and it was suggested that these mechanisms may play a role in the protective effects of PZ51 on cortical neurons of SHRsp.


Assuntos
Antioxidantes/farmacologia , Azóis/farmacologia , Córtex Cerebral/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Compostos Organosselênicos/farmacologia , Acidente Vascular Cerebral/prevenção & controle , Animais , Pressão Sanguínea , Western Blotting , Peso Corporal , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Hipertensão/complicações , Isoindóis , Malondialdeído/metabolismo , Microscopia Eletrônica de Transmissão , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/ultraestrutura , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Tamanho do Órgão , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
6.
Blood Press ; 14(6): 366-72, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16403691

RESUMO

BACKGROUND: To investigate whether extrinsic antioxidant seleno-glutathione peroxidase mimic ebselen (PZ51) can protect endothelium and vascular structure of stroke-prone spontaneously hypertensive rats (SHRsp) during the chronic process of hypertension. METHODS: Twenty-two 8-week-old SHRsp were randomized into a PZ51 group and a control group, and administered by gavage for 6 weeks. We examined the level of nitric oxide (NO) and malonaldehyde (MDA) in plasma. The intima-media thickness (IMT) of the common carotid artery (CCA) was measured by an image-analysis system. The endothelium of the CCA was observed by scanning electron microscopy. The eNOS protein of the major artery was assayed by immunohistochemistry and western blotting. RESULTS: Compared with the control group, PZ51 decreased plasma MDA (7.88+/-1.06 vs 10.88+/-1.73 nmol/l, p<0.001) and increased plasma NO (40.02+/-9.74 vs 22.22+/-10.05 micromol/l, p<0.001), increased eNOS protein expression (8.25+/-2.36 vs 4.46+/-3.14, p=0.026), decreased IMT (69.85+/-5.47 vs 76.60+/-6.53 microm, p<0.05) significantly and alleviated the damage to the endothelium of the CCA. CONCLUSION: Administration of PZ51 for 6 weeks can protect the endothelium and inhibit vascular remodeling, maybe due to its suppression of lipid peroxide formation and increase in eNOS protein expression.


Assuntos
Antioxidantes/farmacologia , Azóis/farmacologia , Endotélio Vascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Compostos Organosselênicos/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Western Blotting , Peso Corporal/efeitos dos fármacos , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/sangue , Hipertensão/enzimologia , Imuno-Histoquímica , Isoindóis , Malondialdeído/sangue , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo III/biossíntese , Ratos , Ratos Endogâmicos SHR , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/patologia
7.
Circ J ; 67(2): 159-62, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12548000

RESUMO

It has been verified that losartan has beneficial effects on ventricular remodeling (VRM) after acute myocardial infarction (AMI), but the effects of carvedilol alone or in combination with losartan on this condition have not been defined. The present study used rats to compare the effects of carvedilol and losartan alone and in combination for preventing VRM after AMI. After ligation of the left coronary artery, 100 surviving female Sprague-Dawley rats were randomly assigned to 1 of 4 groups: (1) AMI control (n=25), (2) carvedilol (Car, 1 mg x kg(-1) x day(-1)) (n=25), (3) losartan (Los, 3 mg x kg(-1) x day (-1)) (n=25), and (4) Car (1 mg x kg (-1). day(-1)) + Los (3 mg x kg(-1) x day (-1)) (n=25). A sham-operated group (n=17) was also randomly selected. Drugs were administered by gastric gavage for 4 weeks. After hemodynamic studies, the hearts were fixed and analyzed pathologically. Exclusive of the rats that had died or had an infarct size <35% or >55%, complete data were obtained for 65 rats, comprising AMI control (n=13), Car (n=12), Los (n=13), combination (n=14), and sham (n=13) groups. There were no significant differences in the size of infarct among the 4 AMI groups (45.8 approximately 46.7%, all p>0.05). Compared with the sham group, left ventricular (LV) end-diastolic pressure (LVEDP), volume (LVV), weight (LVW) and septal thickness (STh) were all significantly increased (all p<0.001), whereas +/-dp/dt was significantly decreased (both p<0.001) in the AMI group. In comparison with the AMI group, LVEDP, LVV, LVW and STh were all significantly decreased (LVEDP: 12.7+/-2.3, 9.7+/-2.8, and 8.6+/-3.5 mmHg vs 20.6+/-2.7 mmHg, all p<0.001; LVV: 0.74+/-0.07, 0.76+/-0.07, and 0.70+/-0.09 ml vs 0.86+/-0.05 ml, all p<0.05; LVW: 668.4+/-52.0, 702.6+/-45.4, and 683.9+/-67.7 mg vs 787.3+/-76.7 mg, p<0.05 approximately 0.001; STh: 1.57+/-0.05, 1.48+/-0.07, and 1.46+/-0.07 mm vs 1.71+/-0.04 mm, all p<0.05), whereas +/-dp/dt was significantly increased (all p<0.05) in the Car, Los, and combination groups, with LVEDP decreasing more in both Los and the combination groups than in the Car group alone (p<0.05) and STh decreasing more in the combination group than in the Car group alone (p<0.05). Carvedilol and losartan alone and in combination all prevent VRM after AMI in rats, with almost equivalent effect.


Assuntos
Carbazóis/farmacologia , Losartan/farmacologia , Infarto do Miocárdio/complicações , Propanolaminas/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Carbazóis/administração & dosagem , Carvedilol , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Feminino , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Hemodinâmica/efeitos dos fármacos , Losartan/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Propanolaminas/administração & dosagem , Ratos , Ratos Sprague-Dawley
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