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1.
Georgian Med News ; (298): 42-46, 2020 Jan.
Artigo em Russo | MEDLINE | ID: mdl-32141846

RESUMO

The main initiator of the development of PAH is the development of endothelial dysfunction of the pulmonary vessels. The cause of this dysfunction is associated with functional disorders of the serotonin system. This research is devoted to study the role of the serotonin system in the development mechanism of PAH in children with CHD. We examined 30 young children (from 1 month to 2 years) with congenital heart defects (CHD), which were divided into 3 groups: group I - 12 children with CHD complicated by pulmonary arterial hypertension (PAH); Group II - 9 children with CHD, not complicated by PAH; Group III - 9 relatively healthy children (control). The serotonin content of platelets, serum and serotonin transporter (SERT) in platelets was determined. To determine serotonin and its carrier, a quantitative enzyme-linked immunosorbent assay (Elisa kit) was used. The study was performed using the Serotonin ELISA diagnostic kit, IBL Hamburg at the automatic ELISA of the Evolis robotic station (BioRad). The results of our studies showed a pronounced (p <0.001) increase in SERT concentration in platelets in the group of children with CHD complicated by PAH compared with the group of children with CHD and the control group. The amount of serotonin in serum tended to increase in this group compared with the control groups and CHD, and the amount of serotonin in platelets tended to decrease. It is likely that an increase in the serotonin transporter in platelets against the background of an increase in serotonin in the blood plasma and a decrease in serotonin in the platelets indicates the inadequacy of SERT activity as a serotonin carrier. However, by activating the proliferation of smooth muscle cells in the pulmonary artery, SERT leads to the development of PAH in children with congenital heart defects. It is necessary to continue research in this direction, which will reveal the molecular mechanisms by which SERT regulates PASMC proliferation and clarify the role of serotonin and its transporter in the development of PAH in children with CHD.


Assuntos
Plaquetas/metabolismo , Cardiopatias Congênitas/complicações , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/etiologia , Artéria Pulmonar/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/sangue , Serotonina/sangue , Biomarcadores/sangue , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/fisiopatologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar
2.
Cell Prolif ; 53(2): e12742, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31943454

RESUMO

OBJECTIVES: Hypoxia is an important risk factor for pulmonary arterial remodelling in pulmonary arterial hypertension (PAH), and the Janus kinase 2 (JAK2) is believed to be involved in this process. In the present report, we aimed to investigate the role of JAK2 in vascular smooth muscle cells during the course of PAH. METHODS: Smooth muscle cell (SMC)-specific Jak2 deficient mice and their littermate controls were subjected to normobaric normoxic or hypoxic (10% O2 ) challenges for 28 days to monitor the development of PAH, respectively. To further elucidate the potential mechanisms whereby JAK2 influences pulmonary vascular remodelling, a selective JAK2 inhibitor was applied to pre-treat human pulmonary arterial smooth muscle cells (HPASMCs) for 1 hour followed by 24-hour hypoxic exposure. RESULTS: Mice with hypoxia-induced PAH were characterized by the altered JAK2/STAT3 activity in pulmonary artery smooth muscle cells. Therefore, induction of Jak2 deficiency in SMCs protected mice from hypoxia-induced increase of right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodelling. Particularly, loss of Jak2 significantly attenuated chronic hypoxia-induced PASMC proliferation in the lungs. Similarly, blockade of JAK2 by its inhibitor, TG-101348, suppressed hypoxia-induced human PASMC proliferation. Upon hypoxia-induced activation, JAK2 phosphorylated signal transducer and activator of transcription 3 (STAT3), which then bound to the CCNA2 promoter to transcribe cyclin A2 expression, thereby promoting PASMC proliferation. CONCLUSIONS: Our studies support that JAK2 could be a culprit contributing to the pulmonary vascular remodelling, and therefore, it could be a viable target for prevention and treatment of PAH in clinical settings.


Assuntos
Proliferação de Células/fisiologia , Hipóxia/metabolismo , Janus Quinase 2/antagonistas & inibidores , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipóxia/patologia , Janus Quinase 2/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Inibidores de Proteínas Quinases/farmacologia , /metabolismo , Artéria Pulmonar/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/fisiologia
3.
Life Sci ; 239: 116928, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31682848

RESUMO

AIM: The dysfunction of human pulmonary arterial smooth muscle cells (HPASMCs) has been suggested to participate in the pathophysiology of pulmonary arterial hypertension (PAH). This study determined miR-19a expression in hypoxia-induced HPASMCs and explored the mechanistic actions of miR-19a in hypoxia-induced HPASMC proliferation and migration. METHODS: QRT-PCR and western blot assays respectively determined the mRNA and protein expression of miR-19a, phosphatase and tensin homolog (PTEN) and hypoxia-inducible factor-1 alpha (HIF-1α). In vitro functional assays determined HPASMC proliferation and migration, respectively. Luciferase reporter assay determined interaction between miR-19a and PTEN. The knockdown effects of miR-19a on PAH were confirmed in in vivo mice model. RESULTS: Hypoxia treatment time-dependently up-regulated miR-19a expression and enhanced cell proliferation in HPASMCs. MiR-19a overexpression increased cell proliferation and migration of HPASMCs, while repression of miR-19a reduced cell proliferative and migratory potentials of hypoxia-treated HPASMCs. Bioinformatics analysis and luciferase reporter assay showed that PTEN 3' untranslated region was targeted by miR-19a, and miR-19a repressed the mRNA and protein expression of PTEN in HPASMCs. Further rescue studies revealed that miR-19a regulated proliferative and migratory potentials of hypoxia-treated HPASMCs via suppressing PTEN expression. In addition, HIF-1α was identified as one of the mediators for the hypoxia-induced aberrant expression levels of miR-19a and PTEN. MiR-19a overexpression enhanced PI3K/AKT signaling, which was attenuated by enforced expression of PTEN in HPASMCs. More importantly, knockdown of miR-19 attenuated the chronic hypoxia-induced PAH in in vivo mice model. CONCLUSION: This study presented a novel mechanistic action of miR-19a-mediated cell proliferation and migration of HPASMCs.


Assuntos
MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Artéria Pulmonar/metabolismo , Animais , Apoptose , Hipóxia Celular/genética , Hipóxia Celular/fisiologia , Linhagem Celular , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipóxia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Músculo Liso/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais
4.
Nutr Metab Cardiovasc Dis ; 29(12): 1418-1428, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31653519

RESUMO

BACKGROUND AND AIMS: Intrauterine growth restriction (IUGR) is a state of slower fetal growth usually followed by a catch-up growth. Postnatal catch-up growth in IUGR models increases the incidence of pulmonary arterial hypertension in adulthood. Here, we hypothesize that the adverse pulmonary vascular consequences of IUGR may be improved by slowing down postnatal growth velocity. Meanwhile, cognitive function was also studied. METHODS AND RESULTS: We established an IUGR rat model by restricting maternal food throughout gestation. After birth, pups were fed a regular or restricted diet during lactation by changing litter size. Thus, there were three experimental groups according to the dam/offspring diet: C/C (gold standard), IUGR with catch-up growth (R/C) and IUGR with delayed growth (R/D). In adulthood (14 weeks of age), we assessed pulmonary vascular development by hemodynamic measurement and immunohistochemistry. Our results showed that adult R/C offspring developed an elevated mean pulmonary arterial pressure (mPAP) and pulmonary arteriolar remodeling accompanied with decreased eNOS mRNA and protein expressions compared to C/C or R/D offspring. This suggested that delayed postnatal growth improved pulmonary circulation compared to postnatal catch-up growth. Conversely, adult R/D offspring performed poorly in cognition. Behavior test and electrophysiology results exhibited a reduced synaptic plasticity. Furthermore, decreased mRNA expression levels of the memory-related gene zif268 and transcription factor recruitment factor p300 in the hippocampus region were also observed in R/D group. CONCLUSION: These findings indicate that delayed postnatal growth results in cognitive impairment, but it reverses elevations in mPAP induced by postnatal catch-up growth following IUGR.


Assuntos
Comportamento Animal , Encéfalo/crescimento & desenvolvimento , Restrição Calórica/efeitos adversos , Cognição , Disfunção Cognitiva/etiologia , Retardo do Crescimento Fetal/dietoterapia , Hipertensão Pulmonar/prevenção & controle , Artéria Pulmonar/crescimento & desenvolvimento , Fatores Etários , Fenômenos Fisiológicos da Nutrição Animal , Animais , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Retardo do Crescimento Fetal/psicologia , Hemodinâmica , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Masculino , Plasticidade Neuronal , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Artéria Pulmonar/metabolismo , Ratos Sprague-Dawley , Remodelação Vascular , Ganho de Peso
5.
Med Sci Monit ; 25: 5738-5746, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31373336

RESUMO

BACKGROUND miR-214-3p has been found to inhibit proliferation and migration in cancer cells. The objective of this study was to determine whether ARHGEF12 is involved in miR-214-3p-mediated suppression of proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). MATERIAL AND METHODS PASMCs were cultured under normoxia or hypoxia. miR-214-3p mimics or inhibitors were transiently transfected into PASMCs. Proliferation, apoptosis, and migration of PASMCs were evaluated using MTT assay, flow cytometry, and Boyden chamber apparatus. Western blot analysis was used to examine expression of Rho guanine nucleotide exchange factor 12 (ARHGEF12), c-fos, c-jun, and caspase-3. Luciferase reporter assay was used to test the direct regulation of miR-214-3p on the 3'-untranslated region (UTR) of ARHGEF12. RESULTS miR-214-3p was significantly upregulated in hypoxia-treated PASMCs. Knockdown of miR-214-3p significantly attenuated hypoxia-induced proliferation and migration in PASMCs and promoted apoptosis, whereas this effect was aggravated by overexpression of miR-214-3p. In addition, dual-luciferase reporter assay demonstrated that ARHGEF12 is a direct target gene of miR-214-3p. The protein levels of ARHGEF12 were downregulated after knockdown of miR-214-3p in PASMCs. Rescue experiment results indicated that decreased proliferation of PASMCs resulted from knockdown of miR-214-3p were partially reversed by silencing of ARHGEF12 by siRNA. Furthermore, knockdown of miR-214-3p reduced expression of c-jun and c-fos, but increased expression of caspase-3 in PASMCs under hypoxia. CONCLUSIONS In conclusion, these results indicate that miR-214-3p acts as a novel regulator of hypoxia-induced proliferation and migration by directly targeting ARHGEF12 and dysregulating c-jun and c-fos in PASMCs, and may be a potential therapeutic target for treating pulmonary hypertension.


Assuntos
Hipóxia Celular/fisiologia , MicroRNAs/metabolismo , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/metabolismo , Animais , Apoptose/fisiologia , Hipóxia Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , MicroRNAs/genética , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Cultura Primária de Células , Artéria Pulmonar/citologia , Ratos , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo
6.
J Biochem Mol Toxicol ; 33(10): e22380, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31339623

RESUMO

Lung endothelial barrier dysfunction leads to severe pathologies, including the lethal Acute Respiratory Distress Syndrome. P53 has been associated with anti-inflammatory activities. The current study employs a variety of unfolded protein response (UPR) activators and inhibitors to investigate the regulation of P53 by UPR in lung cells. The bovine cells that were exposed to the UPR inductors brefeldin A, dithiothreitol, and thapsigargin; demonstrated elevated expression levels of P53 compared to the vehicle-treated cells. On the contrary, the UPR inhibitors N-acetyl cysteine, kifunensine, and ATP-competitive IRE1α kinase-inhibiting RNase attenuator; produced the opposite effects. The outcomes of the present study reveal a positive regulation between UPR and P53. Since it has been shown that a mild induction of the unfolded protein response opposes inflammation, we suggest that P53 is involved in those protective activities in the lung.


Assuntos
Genes p53 , Artéria Pulmonar/metabolismo , Resposta a Proteínas não Dobradas , Acetilcisteína/farmacologia , Alcaloides/farmacologia , Animais , Brefeldina A/farmacologia , Bovinos , Células Cultivadas , Ditiotreitol/farmacologia , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , Tapsigargina/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos
7.
Acta Pharmacol Sin ; 40(10): 1322-1333, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31316183

RESUMO

Abnormal wound healing by pulmonary artery smooth muscle cells (PASMCs) promotes vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Increasing evidence shows that both the mammalian target of rapamycin complex 1 (mTORC1) and nuclear factor-kappa B (NF-κB) are involved in the development of HPH. In this study, we explored the crosstalk between mTORC1 and NF-κB in PASMCs cultured under hypoxic condition and in a rat model of hypoxia-induced pulmonary hypertension (HPH). We showed that hypoxia promoted wound healing of PASMCs, which was dose-dependently blocked by the mTORC1 inhibitor rapamycin (5-20 nM). In PASMCs, hypoxia activated mTORC1, which in turn promoted the phosphorylation of NF-κB. Molecular docking revealed that mTOR interacted with IκB kinases (IKKs) and that was validated by immunoprecipitation. In vitro kinase assays and mass spectrometry demonstrated that mTOR phosphorylated IKKα and IKKß separately. Inhibition of mTORC1 decreased the level of phosphorylated IKKα/ß, thus reducing the phosphorylation and transcriptional activity of NF-κB. Bioinformatics study revealed that dipeptidyl peptidase-4 (DPP4) was a target gene of NF-κB; DPP4 inhibitor, sitagliptin (10-500 µM) effectively inhibited the abnormal wound healing of PASMCs under hypoxic condition. In the rat model of HPH, we showed that NF-κB activation (at 3 weeks) was preceded by mTOR signaling activation (after 1 or 2 weeks) in lungs, and administration of sitagliptin (1-5 mg/kg every day, ig) produced preventive effects against the development of HPH. In conclusion, hypoxia activates the crosstalk between mTORC1 and NF-κB, and increased DPP4 expression in PASMCs that leads to vascular remodeling. Sitagliptin, a DPP4 inhibitor, exerts preventive effect against HPH.


Assuntos
Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Administração Oral , Animais , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Biologia Computacional , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , NF-kappa B/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Cicatrização/efeitos dos fármacos
8.
Life Sci ; 231: 116580, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31216440

RESUMO

AIMS: Chemerin has been recently identified as a vasoactive adipokine implicated in blood pressure regulation. In this context, we evaluated whether chemerin could influence pulmonary vasoreactive response. MATERIALS AND METHODS: Vascular reactivity to chemerin and to phenylephrine, serotonin and endothelin-1 after chemerin pretreatment was evaluated in rat isolated pulmonary artery versus thoracic aorta with and without endothelium. Vasoreactivity to acetylcholine in presence of nitric oxide (NO)-synthase inhibitor (L-NAME) and to NO donor sodium nitroprusside (SNP) was evaluated in chemerin-pretreated pulmonary artery versus thoracic aorta with endothelium. Pretreatment with ODQ, a soluble guanylate cyclase inhibitor and apocynin, a ROS production inhibitor, were also tested. Arteries and lung tissue were harvested for pathobiological evaluation. KEY FINDINGS: Chemerin contracted endothelium-denuded pulmonary artery, while no response was observed in arteries with endothelium. Chemerin potentiated phenylephrine-, endothelin-1- and serotonin-induced vasoconstriction, which was further enhanced by endothelium removal. Chemerin decreased acetylcholine-induced vasorelaxation in arteries with endothelium, while it did not affect SNP-induced relaxation. In presence of L-NAME, there remained a vasorelaxation in chemerin-pretreated arteries. Chemerin or ODQ alone partly decreased acetylcholine-induced vasorelaxation in pulmonary artery and thoracic aorta, while combined chemerin and ODQ incubation abolished it. Treatment with apocynin partly or totally reversed chemerin effects. In both types of arteries, chemerin reduced acetylcholine-induced NO production, as well as endothelial and inducible NO-synthase expression. SIGNIFICANCE: Chemerin potentiates vascular responses to vasoconstrictors in pulmonary artery and thoracic aorta and, impairs acetylcholine-induced pulmonary artery vasodilatation, by mechanisms involving at least partly NO signaling and oxidative stress.


Assuntos
Quimiocinas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Artéria Pulmonar/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Acetilcolina/farmacologia , Adipocinas/metabolismo , Animais , Quimiocinas/metabolismo , Endotelina-1/metabolismo , Endotelinas/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Nitroprussiato/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenilefrina/farmacologia , Artéria Pulmonar/metabolismo , Ratos , Ratos Wistar , Serotonina/metabolismo , Artérias Torácicas/efeitos dos fármacos , Artérias Torácicas/metabolismo , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos
9.
J Recept Signal Transduct Res ; 39(1): 39-44, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31237798

RESUMO

Background: This study is to investigate the roles of muscarinic receptor 3 (M3 receptor) in the effect of penehyclidine hydrochloride (PHC) upregulated beta-arrestin-1 expression in lipopolysaccharide (LPS)-stimulated human pulmonary microvascular endothelial cell (HPMVEC). Methods: HPMVECs were transfected with a shRNA-containing plasmid that specifically targets M3 receptor mRNA. Cells were collected to measure F-actin contents, levels of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), as well as changes of F-actin cytoskeleton arrangement by Laser scanning confocal. Beta-arrestin-1 protein expressions were determined by Western blot and beta-arrestin-1 mRNA expressions were measured by Real-time PCR. Results: Similar to normal cells, PHC could also increase F-actin contents and beta-arrestin-1 expressions, reduce ICAM-1 and VCAM-1 expressions, and inhibit LPS-stimulated reorganization of F-actin and formation of stress fiber in M3 receptor shRNA group. Compared with normal cells, F-actin cytoskeleton was neat, ICAM-1 and VCAM-1 expressions were decreased, as well as F-actin contents were increased in M3 receptor shRNA group. However, there were no differences in beta-arrestin-1 expressions between normal cell groups and M3 receptor shRNA groups. Conclusion: These results indicate that M3 receptor plays an important role in pulmonary microvascular endothelial barrier function, and knock-out of M3 receptor could attenuate LPS-induced pulmonary microvascular endothelial injury. However, upregulative effect of PHC on beta-arrestin-1 expression is independent with presence of M3 receptor.


Assuntos
Endotélio Vascular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Artéria Pulmonar/metabolismo , Quinuclidinas/farmacologia , Receptor Muscarínico M3/metabolismo , beta-Arrestina 1/metabolismo , Actinas/metabolismo , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos
10.
J Vasc Res ; 56(4): 204-214, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31189158

RESUMO

The reduced expression and function of voltage-dependent potassium (KV) channels have been involved in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH), leading to pulmonary vasoconstriction and vascular remodeling, while the upregulation of KV channels is of therapeutic significance for pulmonary hypertension. Beraprost sodium (BPS) has been shown to be effective in patients with pulmonary hypertension. However, the effect of BPS on O2-sensitive KV channels in pulmonary artery smooth muscle cells (PASMCs) remains unclear. In the present study, the effect of BPS on rats with HPH was observed, and the influence of BPS on the expression and function of O2-sensitive KV channels in PASMCs was investigated. The results revealed that BPS reduced mean pulmonary artery pressure, suppressed right ventricular hypertrophy, and attenuated the remodeling of pulmonary arteries in rats exposed to discontinuous hypoxia for 4 weeks (8 h/day). This was accompanied with the significantly upregulated expression of KV channel α-subunits (KV1.2, KV1.5 and KV2.1) and O2-sensitive voltage-gated K+ (KV) channel current (IK(V)) in small pulmonary arteries in HPH model rats, as well as in hypoxia-induced PASMCs. Furthermore, in vitrostudies have revealed that the upregulation of BPS on O2-sensitive KV channels was significantly inhibited after treatment with prostaglandin E2 receptor subtype EP4 antagonist GW627368X. Taken together, these results suggest that BPS attenuates the development of HPH through the upregulation of O2-sensitive KV channels, which was probably via the EP4 receptor-related pathway.


Assuntos
Anti-Hipertensivos/farmacologia , Epoprostenol/análogos & derivados , Hipóxia/complicações , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Receptores de Prostaglandina E Subtipo EP4/agonistas , Vasodilatadores/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Epoprostenol/farmacologia , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Oxigênio/metabolismo , /fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Transdução de Sinais , Regulação para Cima , Remodelação Vascular/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacos
11.
Bull Exp Biol Med ; 167(2): 247-249, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31243672

RESUMO

NO-mediated vasodilatation can be realized via two pathways: dependent and independent on soluble guanylate cyclase; the latter is implemented through NO interaction with ionic channels. We evaluated the contribution of these pathways into NO-induced relaxation of isolated pulmonary arteries in rats. In pulmonary arteries, in contrast to systemic vessels, soluble guanylate cyclase-independent mechanisms is more important, because it mediates relaxation in response to low concentrations of NO donor. The role of soluble guanylate cyclase-dependent mechanisms in the mechanisms of vasodilatation increases with increasing NO donor concentrations.


Assuntos
Óxido Nítrico/metabolismo , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiologia , Animais , GMP Cíclico/metabolismo , Guanilato Ciclase/metabolismo , Masculino , Doadores de Óxido Nítrico/metabolismo , Canais de Potássio/metabolismo , Ratos , Guanilil Ciclase Solúvel/metabolismo , Vasodilatação/fisiologia
12.
Drug Des Devel Ther ; 13: 1843-1853, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213772

RESUMO

Background: To evaluate the effects of resveratrol to monocyte chemoattractant protein-1 (MCP-1) and the role of p38 mitogen-activated protein kinase (MAPK) in this process in vitro. Materials and methods: Animal acute pulmonary thromboembolism (PTE) model: rat model was established by infusion of an autologous blood clot into the pulmonary artery through a polyethylene catheter. One hundred and thirty-two rats were randomly and equally divided into ten groups: rats-control (untreated), rats-1% DMSO, rats-TNF-α, rats-TNF-α + resveratrol, rats-TNF-α +C1142, rats-TNF-α+SB203580, rats-TNF-α+resveratrol + SB203580, rats-resveratrol only, rats-C1142 only, and rats-SB203580 only. Rat pulmonary artery endothelial cells (RPAs) tests: RPAs were isolated from above animal and designated as: RPAs-control, RPAs-1% DMSO control, RPAs-TNF-α, RPAs-TNF-α + resveratrol, RPAs-TNF-α + C1142, RPAs-TNF-α + SB203580, RPAs-TNF-α + resveratrol + SB203580, RPAs-resveratrol only, RPAs-C1142 only, and RPAs-SB203580 only. Each group was further divided into 1, 4, and 8 hrs time point for evaluation (n=6 rats per time point) except RPAs-TNF-α + SB203580, RPAs-TNF-α + resveratrol + SB203580, RPAs-C1142 and RPAs-SB203580 only, which were evaluated at 8 hrs time point. At each time point, mRNA and protein expressions of RPAs of MCP-1 were measured. The phosphorylation of p38 MAPK (p-pMAPK) of RPAs was also detected. Results: We found that the RPAs-TNF-α elicited significant increases in MCP-1 expression and phosphorylation of p38 mitogen-activated protein kinase (p-p38 MAPK). Furthermore, the MCP-1 expressions of RPAs-Resveratrol, RPAs-C1142, and RPAs-SB203580 were significantly down-regulated, which was associated with robustly suppressed TNF-α-induced p-p38MAPK expression. Conclusion: Our findings suggested that MCP-1 was involved in the formation of TNF-α-induced inflammatory response, and resveratrol could down-regulate the expression of MCP-1 via TNF-α- inhibition, which might contribute to the decline of acute PTE-induced PH in vivo.


Assuntos
Quimiocina CCL2/biossíntese , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Masculino , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley
13.
Mol Med Rep ; 20(1): 236-244, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115541

RESUMO

Pulmonary arterial hypertension (PAH) is a fatal and currently incurable cardiopulmonary disease. Numerous microRNAs (miRNAs) serve important roles in the development of PAH. While the expression of miR­30a­5p was downregulated in the lung tissue of rats in a pulmonary hypertension rat model, the expression pattern and function of miR­30a­5p in human PAH remain unclear. Reverse transcription quantitative polymerase chain reaction (RT­qPCR) was used to examine miR­30a­5p and chitinase­3­like protein 1 (YKL­40) mRNA expression levels. The expression levels of YKL­40 and apoptosis­associated proteins were measured by western blot analysis. Cell proliferation assays and flow cytometry analysis were performed to examine cell proliferation and apoptosis, respectively. The association between miR­30a­5p and YKL­40 was determined by a luciferase reporter assay, RT­qPCR and western blot analysis. The relative expression levels of miR­30a­5p in plasma were increased in patients with PAH [median=13.23 (25th percentile=6.388, 75th percentile=21.91)] compared with normal controls [median=2.25 (25th percentile=1.4, 75th percentile=3.7). The expression of miR­30a­5p was significantly downregulated while the protein expression of YKL­40 was significantly upregulated in hypoxia­induced human pulmonary artery endothelial cells (HPAECs) when compared with the hypoxia­induced group at 0 h. miR­30a­5p overexpression promoted HPAEC growth and inhibited apoptosis of HPAECs under hypoxia. A miR­30a­5p mimic decreased the luciferase activity of a luciferase reporter construct containing YKL­40 3'­untranslated region and also decreased YKL­40 protein expression. YKL­40 overexpression partly alleviated the effects of miR­30a­5p upregulation on proliferation and apoptosis of HPAECs under hypoxia. In conclusion, the data indicated that miR­30a­5p promoted cell growth and inhibited apoptosis of HPAECs under hypoxia by targeting YKL­40. Therefore, the miR­30a­5p/YKL­40 axis may provide a potential target for the development of novel PAH therapies.


Assuntos
Proteína 1 Semelhante à Quitinase-3/genética , Hipertensão Pulmonar/genética , MicroRNAs/genética , Animais , Apoptose/genética , Hipóxia Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Regulação da Expressão Gênica/genética , Humanos , Hipertensão Pulmonar/patologia , Pulmão/metabolismo , Pulmão/patologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos
14.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083380

RESUMO

Mitochondria-associated membranes (MAM) are a well-recognized contact link between the mitochondria and endoplasmic reticulum that affects mitochondrial biology and vascular smooth muscle cells (VSMCs) proliferation via the regulation of mitochondrial Ca2+(Ca2+m) influx. Nogo-B receptor (NgBR) plays a vital role in proliferation, epithelial-mesenchymal transition, and chemoresistance of some tumors. Recent studies have revealed that downregulation of NgBR, which stimulates the proliferation of VSMCs, but the underlying mechanism remains unclear. Here, we investigated the role of NgBR in MAM and VSMC proliferation. We analyzed the expression of NgBR in pulmonary arteries using a rat model of hypoxic pulmonary hypertension (HPH), in which rats were subjected to normoxic recovery after hypoxia. VSMCs exposed to hypoxia and renormoxia were used to assess the alterations in NgBR expression in vitro. The effect of NgBR downregulation and overexpression on VSMC proliferation was explored. The results revealed that NgBR expression was negatively related with VSMCs proliferation. Then, MAM formation and the phosphorylation of inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) was detected. We found that knockdown of NgBR resulted in MAM disruption and augmented the phosphorylation of IP3R3 through pAkt, accompanied by mitochondrial dysfunction including decreased Ca2+m, respiration and mitochondrial superoxide, increased mitochondrial membrane potential and HIF-1α nuclear localization, which were determined by confocal microscopy and Seahorse XF-96 analyzer. By contrast, NgBR overexpression attenuated IP3R3 phosphorylation and HIF-1α nuclear localization under hypoxia. These results reveal that dysregulation of NgBR promotes VSMC proliferation via MAM disruption and increased IP3R3 phosphorylation, which contribute to the decrease of Ca2+m and mitochondrial impairment.


Assuntos
Membranas Mitocondriais/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Proteínas Nogo/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular , Proliferação de Células , Regulação para Baixo , Retículo Endoplasmático/metabolismo , Hipertensão Pulmonar , Hipóxia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Modelos Biológicos , Miócitos de Músculo Liso/ultraestrutura , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/metabolismo , Ratos , Transdução de Sinais
15.
PLoS Genet ; 15(5): e1008163, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31091229

RESUMO

As small regulatory transcripts, microRNAs (miRs) act as genetic 'fine tuners' of posttranscriptional events, and as genetic switches to promote phenotypic switching. The miR miR26a targets the BMP signalling effector, smad1. We show that loss of miR26a leads to hemorrhage (a loss of vascular stability) in vivo, suggesting altered vascular differentiation. Reduction in miR26a levels increases smad1 mRNA and phospho-Smad1 (pSmad1) levels. We show that increasing BMP signalling by overexpression of smad1 also leads to hemorrhage. Normalization of Smad1 levels through double knockdown of miR26a and smad1 rescues hemorrhage, suggesting a direct relationship between miR26a, smad1 and vascular stability. Using an in vivo BMP genetic reporter and pSmad1 staining, we show that the effect of miR26a on smooth muscle differentiation is non-autonomous; BMP signalling is active in embryonic endothelial cells, but not in smooth muscle cells. Nonetheless, increased BMP signalling due to loss of miR26a results in an increase in acta2-expressing smooth muscle cell numbers and promotes a differentiated smooth muscle morphology. Similarly, forced expression of smad1 in endothelial cells leads to an increase in smooth muscle cell number and coverage. Furthermore, smooth muscle phenotypes caused by inhibition of the BMP pathway are rescued by loss of miR26a. Taken together, our data suggest that miR26a modulates BMP signalling in endothelial cells and indirectly promotes a differentiated smooth muscle phenotype. Our data highlights how crosstalk from BMP-responsive endothelium to smooth muscle is important for smooth muscle differentiation.


Assuntos
Células Endoteliais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Receptores de Proteínas Morfogenéticas Ósseas/genética , Receptores de Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular , Endotélio , Regulação da Expressão Gênica/genética , Músculo Liso Vascular/metabolismo , Artéria Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad1/genética , Proteína Smad1/metabolismo , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
16.
Nutr Metab Cardiovasc Dis ; 29(6): 639-651, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954415

RESUMO

BACKGROUND AND AIMS: Early postnatal life is a critical developmental period that affects health of the whole life. Extrauterine growth restriction (EUGR) causes cardiovascular development problems and diseases, including pulmonary arterial hypertension (PAH). PAH is characterized by proliferation, migration, and anti-apoptosis of pulmonary artery smooth muscle cells (PASMCs). However, the role of PASMCs in EUGR has not been studied. Thus, we hypothesized that PASMCs dysfunction played a role in EUGR-induced pulmonary hypertension. METHODS AND RESULTS: Here we identified that postnatal nutritional restriction-induced EUGR rats exhibited an elevated mean pulmonary arterial pressure and vascular remodeling at 12 weeks old. PASMCs of EUGR rats showed increased cell proliferation and migration features. In EUGR-induced PAH rats, Notch3 signaling was activated. Relative mRNA and protein expression levels of Notch3 intracellular domain (Notch3 ICD), and Notch target gene Hey1 in PASMCs were upregulated. We further demonstrated that pharmacological inhibition of Notch3 activity by using a γ-secretase inhibitor DAPT, which blocked the cleavage of Notch proteins to ICD peptides, could effectively inhibit PASMC proliferation. Specifically knocked down of Notch3 in rat PASMCs by shRNA restored the abnormal PASMC phenotype in vitro. We found that administration of Notch signaling inhibitor DAPT could successfully reduce mean pulmonary arterial pressure in EUGR rats. CONCLUSIONS: The present study demonstrated that upregulation of Notch3 signaling in PASMCs was crucial for the development of EUGR-induced PAH. Blocking Notch3-Hey1 signaling pathway in PASMCs provides a potential therapeutic target for PAH.


Assuntos
Pressão Arterial , Transtornos do Crescimento/complicações , Hipertensão Pulmonar/etiologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Receptor Notch3/metabolismo , Animais , Animais Recém-Nascidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Restrição Calórica , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Transtornos do Crescimento/metabolismo , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Masculino , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Ratos Sprague-Dawley , Receptor Notch3/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Remodelação Vascular
17.
Respir Res ; 20(1): 74, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992021

RESUMO

BACKGROUND: Pulmonary vascular abnormalities are a characteristic feature of chronic obstructive pulmonary disease (COPD). Cigarette smoking is the most important risk factor for COPD. It is believed that its constant exposure triggers endothelial cell damage and vascular remodelling. Under pathological conditions, progenitor cells (PCs) are mobilized from the bone marrow and recruited to sites of vascular injury. The aim of the study was to investigate whether in COPD the number of circulating PCs is related to the presence of bone marrow-derived cells in pulmonary arteries and the association of these phenomena to both systemic and pulmonary endothelial dysfunction. METHODS: Thirty-nine subjects, 25 with COPD, undergoing pulmonary resection because of a localized carcinoma, were included. The number of circulating PCs was assessed by flow cytometry using a triple combination of antibodies against CD45, CD133 and CD34. Infiltrating CD45+ cells were identified by immunohistochemistry in pulmonary arteries. Endothelial function in systemic and pulmonary arteries was measured by flow-mediated dilation and adenosine diphosphate-induced vasodilation, respectively. RESULTS: COPD patients had reduced numbers of circulating PCs (p < 0.05) and increased numbers of CD45+ cells (< 0.05) in the pulmonary arterial wall than non-COPD subjects, being both findings inversely correlated (r = - 0.35, p < 0.05). In pulmonary arteries, the number of CD45+ cells correlated with the severity of vascular remodelling (r = 0.4, p = 0.01) and the endothelium-dependent vasodilation (r = - 0.3, p = 0.05). Systemic endothelial function was unrelated to the number of circulating PCs and changes in pulmonary vessels. CONCLUSION: In COPD, the decrease of circulating PCs is associated with their recruitment in pulmonary arteries, which in turn is associated with endothelial dysfunction and vessel remodelling, suggesting a mechanistic link between these phenomena. Our findings are consistent with the notion of an imbalance between endothelial damage and repair capacity in the pathogenesis of pulmonary vascular abnormalities in COPD.


Assuntos
Movimento Celular/fisiologia , Endotélio Vascular/metabolismo , Artéria Pulmonar/metabolismo , Doença Pulmonar Obstrutiva Crônica/sangue , Células-Tronco/metabolismo , Idoso , Endotélio Vascular/patologia , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/patologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Células-Tronco/patologia
18.
Crit Rev Eukaryot Gene Expr ; 29(1): 69-76, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002596

RESUMO

Pulmonary arterial hypertension (PAH), also known as broilers ascites syndrome, is characterized by hypoxia, pulmonary artery pressure, and right heart failure. However, less information is available about the molecular mechanisms of PAH. We evaluated the mediation of calcium-sensing receptor by inducing hypoxia for the possible proliferation of pulmonary artery smooth muscle cells via the G protein pathway. For this purpose, we used an in vitro trial of chicken cell culture and confirmed our results by using immunohistochemistry, immunofluorescence staining, quantitative real-time polymerase chain reaction assay, and Western blotting analysis. Our results showed that the mRNA and protein expression levels of calcium-sensing receptor (CaSR) were significantly upregulated in cells when co-incubated with CaCl2. However, the levels of mRNA and protein were obviously decreased when supplemented with blocking agents (NiCl2, 2-APB, and D609). Furthermore, the experimentally induced hypoxia also upregulated the expression of CaSR gene as compared to CaSR gene expression in control cells. Together, these results indicate that hypoxia plays an important role in the expression of CaSR gene in pulmonary artery smooth muscle cells and reveals new targets for the CaSR excited hypothesis to prevent and control PAH in chickens.


Assuntos
Hipóxia Celular , Proliferação de Células , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Transdução de Sinais , Animais , Galinhas/metabolismo , Galinhas/fisiologia , Proteínas de Ligação ao GTP/metabolismo , Miócitos de Músculo Liso/fisiologia , /fisiopatologia , Artéria Pulmonar/fisiopatologia
19.
Life Sci ; 227: 64-73, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31004656

RESUMO

AIM: Growing evidence suggests that endothelial-mesenchymal transition (EndMT) play key roles in pulmonary arterial remodeling during pulmonary arterial hypertension (PAH), but the underlying mechanisms have yet to be fully understood. miR-27a has been shown to promote proliferation of pulmonary arterial cells during PAH, but its role in EndMT remains unexplored. This study was designed to investigate the role and underlying mechanism of miR-27a in EndMT during PAH. MAIN METHODS: Rats were exposed in hypoxia (10% O2) for 3 weeks to induce PAH, and human pulmonary artery endothelial cells (HPAECs) were exposed in hypoxia (1% O2) for 48 h to induce EndMT. Immunohistochemistry, in situ hybridization, immunofluorescence, real-time PCR and Western blot were conducted to detect the expressions of RNAs and proteins, and luciferase assay was used to verify the putative binding site of miR-27a. KEY FINDINGS: We found that hypoxia up-regulated miR-27a in the tunica intima of rat pulmonary arteries and HPAECs, and that inhibition of miR-27a suppressed hypoxia-induced EndMT. Furthermore, elevated expression of miR-27a suppressed bone morphogenetic protein (BMP) signaling by targeting Smad5, thereby lessening Id2-mediated repression of the 2 critical mediators of EndMT (Snail and Twist). SIGNIFICANCE: Our data unveiled a novel role of miR-27a in EndMT during hypoxia-induced PAH. Thus, targeting of miR-27a-related pathway may be therapeutically harnessed to treat PAH.


Assuntos
Transição Epitelial-Mesenquimal/genética , Hipertensão Pulmonar/genética , MicroRNAs/fisiologia , Animais , Técnicas de Cultura de Células , Proliferação de Células , Células Endoteliais/metabolismo , Endotélio/metabolismo , Regulação da Expressão Gênica , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipóxia/genética , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Artéria Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Regulação para Cima , Remodelação Vascular/genética
20.
J Biochem Mol Toxicol ; 33(7): e22332, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30974023

RESUMO

Alpha-naphthylthiourea (ANTU), a rodenticide induces lung toxicity. Chrysin a flavonoid possesses antioxidant, anti-inflammatory, and antihypertensive potential. The aim of this study was to evaluate the efficacy of chrysin against ANTU-induced pulmonary edema (PE) and pulmonary arterial hypertension (PAH) in laboratory rats. Sprague-Dawley rats were used to induce PE (ANTU, 10 mg/kg, ip) and PAH (ANTU, 5 mg/kg, ip, 4 weeks). Animals were treated with chrysin (10, 20, and 40 mg/kg) and various biochemical, molecular, and histological parameters were evaluated. Acute administration of ANTU induces PE revealed by significant (P < 0.05) increase in relative lung weight, pleural effusion volume, lung edema, bronchoalveolar lavage fluid cell counts, total protein, 5-hydroxytryptamine (5-HT), lactate dehydrogenase (LDH), and γ-glutamyl transferase (GGT), whereas pretreatment with chrysin (20 and 40 mg/kg, ip) significantly (P < 0.05) attenuated these ANTU-induced biochemical and histological alterations. Repeated administration of ANTU caused induction of PAH evaluated by significant (P < 0.05) alterations in electrocardiographic, hemodynamic changes, and left ventricular function, whereas chrysin (20 and 40 mg/kg, p.o.) treatment significantly (P < 0.05) attenuated these alterations. ANTU-induced hematological and serum biochemical (aspartate transaminase, alanine transaminase, LDH, and creatinine kinase MB) alterations were significantly (P < 0.05) inhibited by chrysin. It also significantly (P < 0.05) decreased elevated levels of oxido-nitrosative stress in the right ventricle (RV) and lung. Chrysin significantly (P < 0.05) attenuated downregulated endothelial nitric oxide synthase and upregulated vascular endothelial growth factor messenger RNA and protein expressions both in the RV and pulmonary artery. Chrysin inhibited ANTU-induced PE and PAH via modulation of inflammatory responses (5-HT, LDH, and GGT), oxido-nitrosative stress, and VEGF and eNOs levels.


Assuntos
Flavonoides/farmacologia , Hipertensão Pulmonar , Óxido Nítrico Sintase Tipo III/biossíntese , Edema Pulmonar , Tioureia/análogos & derivados , Fator A de Crescimento do Endotélio Vascular/biossíntese , Animais , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/prevenção & controle , Pulmão/metabolismo , Pulmão/patologia , Masculino , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Edema Pulmonar/prevenção & controle , Ratos , Ratos Sprague-Dawley , Tioureia/efeitos adversos , Tioureia/farmacologia
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