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1.
Life (Basel) ; 14(7)2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-39063659

RESUMO

Diastolic dysfunction, a prevalent condition characterized by impaired relaxation and filling of the left ventricle, significantly contributes to heart failure with preserved ejection fraction (HFpEF). Galectin-3, a ß-galactoside-binding lectin, has garnered attention as a potential biomarker and mediator of fibrosis and inflammation in cardiovascular diseases. This comprehensive review investigates the impact of galectin-3 on diastolic dysfunction. We explore its molecular mechanisms, including its involvement in cellular signaling pathways and interaction with components of the extracellular matrix. Evidence from both animal models and clinical studies elucidates galectin-3's role in cardiac remodeling, inflammation, and fibrosis, shedding light on the underlying pathophysiology of diastolic dysfunction. Additionally, we examine the diagnostic and therapeutic implications of galectin-3 in diastolic dysfunction, emphasizing its potential as both a biomarker and a therapeutic target. This review underscores the significance of comprehending galectin-3's role in diastolic dysfunction and its promise in enhancing diagnosis and treatment approaches for HFpEF patients.

2.
Medicina (Kaunas) ; 60(6)2024 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-38929484

RESUMO

Cafestol, a bioactive compound found in coffee, has attracted considerable attention due to its potential impact on cardiovascular health. This review aims to comprehensively explore the association between cafestol and cardiovascular diseases. We delve into the mechanisms through which cafestol influences lipid metabolism, inflammation, and endothelial function, all of which are pivotal in cardiovascular pathophysiology. Moreover, we meticulously analyze epidemiological studies and clinical trials to elucidate the relationship between cafestol and cardiovascular outcomes. Through a critical examination of existing literature, we aim to provide insights into the potential benefits and risks associated with cafestol concerning cardiovascular health.


Assuntos
Doenças Cardiovasculares , Humanos , Café , Metabolismo dos Lipídeos/efeitos dos fármacos
3.
Int J Mol Sci ; 24(3)2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36768628

RESUMO

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor and a familiar neuronal marker for nerve injury. This factor has been shown to protect neurons from hypoxic insult in vitro by suppressing carboxyl-terminal modulator protein (CTMP) transcription, and indirectly activating the anti-apoptotic Akt/PKB cascade. Despite prior studies in vitro, whether this neuroprotective pathway also exists in the brain in vivo after ischemic insult remains to be determined. In the present study, we showed a rapid and marked induction of ATF3 mRNA throughout ischemia-reperfusion in a middle cerebral artery (MCA) occlusion model. Although the level of CTMP mRNA was quickly induced upon ischemia, its level showed only a mild increase after reperfusion. With the gain-of-function approach, both pre- and post-ischemic administration of Ad-ATF3 ameliorated brain infarct and neurological deficits. Whereas, with the loss-of-function approach, ATF3 knockout (KO) mice showed bigger infarct and worse functional outcome after ischemia. In addition, these congenital defects were rescued upon reintroducing ATF3 to the brain of KO mice. ATF3 overexpression led to a lower level of CTMP and a higher level of p-Akt(473) in the ischemic brain. On the contrary, ATF3 KO resulted in upregulation of CTMP and downregulation of p-Akt(473) instead. Furthermore, post-ischemic CTMP siRNA knockdown led to smaller infarct and better behaviors. CTMP siRNA knockdown increased the level of p-Akt(473), but did not alter the ATF3 level in the ischemic brain, upholding the ATF3→CTMP signal cascade. In summary, our proof-of-principle experiments support the existence of neuroprotective ATF3→CTMP signal cascade regulating the ischemic brain. Furthermore, these results suggest the therapeutic potential for both ATF3 overexpression and CTMP knockdown for stroke treatment.


Assuntos
Isquemia Encefálica , Proteínas Proto-Oncogênicas c-akt , Camundongos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Proteínas de Transporte/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Camundongos Knockout , Infarto Encefálico/genética , RNA Interferente Pequeno/genética , Infarto Cerebral , Palmitoil-CoA Hidrolase/metabolismo
4.
J Pers Med ; 12(3)2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35330415

RESUMO

Background: This 12-year study aimed to compare the longitudinal change in left ventricular diastolic dysfunction (LVDD) between healthy elderly, coronary artery disease (CAD), and hypertension (HTN) patients. Methods: From 2008 to 2020, 1476 patients were included, and 3181 echocardiography examinations were conducted. Finally, 130 participants (36 healthy elderly (79.39 ± 9.51 years old), 51 with CAD (68.31 ± 12.09 years old), and 43 with HTN (68.31 ± 12.09 years old)) with more than a 10-year follow-up period were included in the final analysis. Results: The change in diastolic function was different among these subjects according to the integrated score index (elderly vs. HTN, p = 0.01; CAD vs. HTN, p = 0.01), septal E/e' ratio (elderly vs. HTN, p < 0.001; CAD vs. HTN, p = 0.01), lateral E/e' ratio (elderly vs. HTN, p < 0.001; CAD vs. HTN, p < 0.001), and NYHA functional class (elderly vs. HTN, p = 0.03; CAD vs. HTN, p < 0.001). Additionally, per one-year increase in age, the integrated score index increased 0.2 in the healthy elderly, 0.15 in the CAD, and 0.06 in the HTN patients (all p < 0.05). Conclusion: Under aggressive treatment, diastolic function was relatively preserved in HTN subjects with aging in comparison with elderly and CAD subjects.

5.
Neuromolecular Med ; 23(1): 199-210, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33025396

RESUMO

Neuroinflammation has been shown to exacerbate ischemic brain injury, and is considered as a prime target for the development of stroke therapies. Clinacanthus nutans Lindau (C. nutans) is widely used in traditional medicine for treating insect bites, viral infection and cancer, due largely to its anti-oxidative and anti-inflammatory properties. Recently, we reported that an ethanol extract from the leaf of C. nutans could protect the brain against ischemia-triggered neuronal death and infarction. In order to further understand the molecular mechanism(s) for its beneficial effects, two experimental paradigms, namely, in vitro primary cortical neurons subjected to oxygen-glucose deprivation (OGD) and in vivo rat middle cerebral artery (MCA) occlusion, were used to dissect the anti-inflammatory effects of C. nutans extract. Using promoter assays, immunofluorescence staining, and loss-of-function (siRNA) approaches, we demonstrated that transient OGD led to marked induction of IL-1ß, IL-6 and TNFα, while pretreatment with C. nutans suppressed production of inflammatory cytokines in primary neurons. C. nutans inhibited IL-1ß transcription via preventing NF-κB/p65 nuclear translocation, and siRNA knockdown of either p65 or IL-1ß mitigated OGD-mediated neuronal death. Correspondingly, post-ischemic treatment of C. nutans attenuated IκBα degradation and decreased IL-1ß, IL-6 and TNFα production in the ischemic brain. Furthermore, IL-1ß siRNA post-ischemic treatment reduced cerebral infarct, thus mimicking the beneficial effects of C. nutans. In summary, our findings demonstrated the ability for C. nutans to suppress NF-κB nuclear translocation and inhibit IL-1ß transcription in ischemic models. Results further suggest the possibility for using C. nutans to prevent and treat stroke patients.


Assuntos
Acanthaceae/química , Anti-Inflamatórios/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Interleucina-1beta/biossíntese , NF-kappa B/metabolismo , Neurônios/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Plantas Medicinais/química , Animais , Anti-Inflamatórios/farmacologia , Morte Celular/efeitos dos fármacos , Células Cultivadas , Infarto Cerebral/patologia , Avaliação Pré-Clínica de Medicamentos , Glucose/farmacologia , Interleucina-1beta/genética , Masculino , Inibidor de NF-kappaB alfa/metabolismo , Oxigênio/farmacologia , Fitoterapia , Regiões Promotoras Genéticas , Transporte Proteico/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/genética , Ratos , Ratos Long-Evans , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética , Transcrição Gênica/efeitos dos fármacos , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética
7.
Am J Chin Med ; 47(2): 337-350, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30871360

RESUMO

Through population-based studies, associations have been found between coffee drinking and numerous health benefits, including a reduced risk of cardiovascular disease. Active ingredients in coffee have therefore received considerable attention from researchers. A wide variety of effects have been attributed to cafestol, one of the major compounds in coffee beans. Because cardiac hypertrophy is an independent risk factor for cardiovascular events, this study examined whether cafestol inhibits urotensin II (U-II)-induced cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were exposed only to U-II (1 nM) or to U-II (1 nM) following 12-h pretreatment with cafestol (1-10 µ M). Cafestol (3-10 µ M) pretreatment significantly inhibited U-II-induced cardiomyocyte hypertrophy with an accompanying decrease in U-II-induced reactive oxygen species (ROS) production. Cafestol also inhibited U-II-induced phosphorylation of redox-sensitive extracellular signal-regulated kinase (ERK) and epidermal growth factor receptor transactivation. In addition, cafestol pretreatment increased Src homology region 2 domains-containing phosphatase-2 (SHP-2) activity, suggesting that cafestol prevents ROS-induced SHP-2 inactivation. Moreover, nuclear factor erythroid-2-related factor 2 (Nrf2) translocation and heme oxygenase-1 (HO-1) expression were enhanced by cafestol. Addition of brusatol (a specific inhibitor of Nrf2) or Nrf2 siRNA significantly attenuated cafestol-mediated inhibitory effects on U-II-stimulated ROS production and cardiomyocyte hypertrophy. In summary, our data indicate that cafestol prevented U-II-induced cardiomycyte hypertrophy through Nrf2/HO-1 activation and inhibition of redox signaling, resulting in cardioprotective effects. These novel findings suggest that cafestol could be applied in pharmacological therapy for cardiac diseases.


Assuntos
Crescimento Celular/efeitos dos fármacos , Diterpenos/farmacologia , Miócitos Cardíacos/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Urotensinas/efeitos adversos , Urotensinas/antagonistas & inibidores , Animais , Cardiomegalia/tratamento farmacológico , Células Cultivadas , Depressão Química , Diterpenos/uso terapêutico , Receptores ErbB/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Heme Oxigenase-1/metabolismo , Fosforilação/efeitos dos fármacos , Fitoterapia , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Ativação Transcricional/efeitos dos fármacos
8.
J Cardiovasc Nurs ; 34(2): 106-114, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30363015

RESUMO

OBJECTIVE: To evaluate whether home or ambulatory blood pressure (BP) monitoring was associated with preclinical hypertensive cardiovascular target organ damage (TOD). METHODS: We enrolled participants with prehypertension and stage 1 hypertension from 11 medical centers within the Taiwan hypertension-associated cardiac disease consortium. Recordings of clinical BP measurement, ambulatory BP monitoring for 24 hours, and home BP monitoring during morning and evening were made. The measured parameters of target organ damage included left ventricular mass index (LVMI), left atrial volume index (LAVI), and carotid-femoral pulse wave velocity (PWV). RESULTS: Data were collected from 561 study participants (mean age, 65.0 ± 10.8 years; men, 61.3%). Morning and evening home BP values were slightly higher than the daytime and nighttime ABP values (difference for systolic morning-daytime/evening-nighttime, 7.3 ± 14.2/11.3 ± 18.5 mm Hg, P < .001; for diastolic, 5.4 ± 9.4/7.3 ± 12.1, P < .001). Daytime ambulatory (r = 0.114), nighttime ambulatory (r = 0.130), morning home (r = 0.310), and evening home (r = 0.220) systolic BPs (SBPs) were all associated with LVMI (all P < .05). The correlation coefficient was significantly greater for the relationship between daytime home SBP and LVMI than for the relationship between ambulatory SBP and LVMI (P < .01). The goodness of fit of the association between SBP and LVMI improved by adding home daytime SBP to the other SBPs (P < .001). Similar findings were observed for LAVI, but not for PWV. CONCLUSION: These findings indicate that morning SBP assessed by home monitoring appears to be a better predictor than other BP measures to determine preclinical hypertensive cardiovascular damage in patients with early-stage hypertension.


Assuntos
Monitorização Ambulatorial da Pressão Arterial , Doenças Cardiovasculares/etiologia , Hipertensão/complicações , Hipertensão/diagnóstico , Pré-Hipertensão/complicações , Pré-Hipertensão/diagnóstico , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
Oxid Med Cell Longev ; 2018: 7861518, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29854096

RESUMO

Moderate coffee consumption is inversely associated with cardiovascular disease mortality; however, mechanisms underlying this causal effect remain unclear. Cafestol, a diterpene found in coffee, has various properties, including an anti-inflammatory property. This study investigated the effect of cafestol on cyclic-strain-induced inflammatory molecule secretion in vascular endothelial cells. Cells were cultured under static or cyclic strain conditions, and the secretion of inflammatory molecules was determined using enzyme-linked immunosorbent assay. The effects of cafestol on mitogen-activated protein kinases (MAPK), heme oxygenase-1 (HO-1), and sirtuin 1 (Sirt1) signaling pathways were examined using Western blotting and specific inhibitors. Cafestol attenuated cyclic-strain-stimulated intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein- (MCP-) 1, and interleukin- (IL-) 8 secretion. Cafestol inhibited the cyclic-strain-induced phosphorylation of extracellular signal-regulated kinase and p38 MAPK. By contrast, cafestol upregulated cyclic-strain-induced HO-1 and Sirt1 expression. The addition of zinc protoporphyrin IX, sirtinol, or Sirt1 silencing (transfected with Sirt1 siRNA) significantly attenuated cafestol-mediated modulatory effects on cyclic-strain-stimulated ICAM-1, MCP-1, and IL-8 secretion. This is the first study to report that cafestol inhibited cyclic-strain-induced inflammatory molecule secretion, possibly through the activation of HO-1 and Sirt1 in endothelial cells. The results provide valuable insights into molecular pathways that may contribute to the effects of cafestol.


Assuntos
Quimiocina CCL2/metabolismo , Diterpenos/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-8/metabolismo , Estresse Fisiológico , Regulação para Cima/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Fosforilação/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Sirtuína 1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
Mol Neurobiol ; 55(7): 5425-5438, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28942553

RESUMO

Clinacanthus nutans Lindau (C. nutans) is a traditional herbal medicine widely used in Asian countries for treating a number of remedies including snake and insect bites, skin rashes, viral infections, and cancer. However, the underlying molecular mechanisms for its action and whether C. nutans can offer protection on stroke damage in brain remain largely unknown. In the present study, we demonstrated protective effects of C. nutans extract to ameliorate neuronal apoptotic death in the oxygen-glucose deprivation model and to reduce infarction and mitigate functional deficits in the middle cerebral artery occlusion model, either administered before or after hypoxic/ischemic insult. Using pharmacological antagonist and siRNA knockdown approaches, we demonstrated ability for C. nutans extract to protect neurons and ameliorate ischemic injury through promoting the anti-apoptotic activity of peroxisome proliferator-activated receptor-gamma (PPAR-γ), a stress-induced transcription factor. Reporter and chromatin immunoprecipitation promoter analysis further revealed C. nutans extract to selectively increase CCAAT/enhancer binding protein (C/EBP)ß binding to specific C/EBP binding site (-332~-325) on the PPAR-γ promoter to augment its transcription. In summary, we report a novel transcriptional activation involving C/EBPß upregulation of PPAR-γ expression to suppress ischemic neuronal apoptosis and brain infarct. Recognition of C. nutans to enhance the C/EBPߠ→ PPAR-γ neuroprotective signaling pathway paves a new way for future drug development for prevention and treatment of ischemic stroke and other neurodegenerative diseases.


Assuntos
Acanthaceae/química , Apoptose , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Neurônios/patologia , PPAR gama/metabolismo , Transcrição Gênica , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos BALB C , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Extratos Vegetais/farmacologia , Ratos , Transcrição Gênica/efeitos dos fármacos
11.
J Biomed Sci ; 24(1): 85, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29141644

RESUMO

BACKGROUND: This study investigated whether lipopolysaccharide (LPS) increase protease-activated receptor-2 (PAR-2) expression and enhance the association between PAR-2 expression and chemokine production in human vascular endothelial cells (ECs). METHODS: The morphology of ECs was observed through microphotography in cultured human umbilical vein ECs (EA. hy926 cells) treated with various LPS concentrations (0, 0.25, 0.5, 1, and 2 µg/mL) for 24 h, and cell viability was assessed using the MTT assay. Intracellular calcium imaging was performed to assess agonist (trypsin)-induced PAR-2 activity. Western blotting was used to explore the LPS-mediated signal transduction pathway and the expression of PAR-2 and adhesion molecule monocyte chemoattractant protein-1 (MCP-1) in ECs. RESULTS: Trypsin stimulation increased intracellular calcium release in ECs. The calcium influx was augmented in cells pretreated with a high LPS concentration (1 µg/mL). After 24 h treatment of LPS, no changes in ECs viability or morphology were observed. Western blotting revealed that LPS increased PAR-2 expression and enhanced trypsin-induced extracellular signal-regulated kinase (ERK)/p38 phosphorylation and MCP-1 secretion. However, pretreatment with selective ERK (PD98059), p38 mitogen-activated protein kinase (MAPK) (SB203580) inhibitors, and the selective PAR-2 antagonist (FSLLRY-NH2) blocked the effects of LPS-activated PAR-2 on MCP-1 secretion. CONCLUSIONS: Our findings provide the first evidence that the bacterial endotoxin LPS potentiates calcium mobilization and ERK/p38 MAPK pathway activation and leads to the secretion of the pro-inflammatory chemokine MCP-1 by inducing PAR-2 expression and its associated activity in vascular ECs. Therefore, PAR-2 exerts vascular inflammatory effects and plays an important role in bacterial infection-induced pathological responses.


Assuntos
Quimiocina CCL2/genética , Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Lipopolissacarídeos/farmacologia , Receptor PAR-2/genética , Transdução de Sinais , Quimiocina CCL2/metabolismo , Relação Dose-Resposta a Droga , Humanos , Receptor PAR-2/metabolismo
12.
Pharmacogenomics ; 18(3): 245-253, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28112575

RESUMO

AIM: This study aimed to determine clinical utility of genotype-guided dosing for warfarin in Han-Chinese. METHODS: A total of 320 patients were randomly assigned International Warfarin Pharmacogenetic Consortium algorithm, Taiwan algorithm and optimal clinical care arms. The primary outcome of the study was the percentage of time in the therapeutic range during the first 90 days of treatment. RESULTS: The percentage of time in the therapeutic range of the clinical care group in the first 2 weeks was significantly higher than the algorithm groups. This difference was no longer observed after 4 weeks. No difference in excessive anticoagulation (international normalized ratio ≥4.0) and adverse events was observed. CONCLUSION: Genotype-guided dosing did not provide significant benefit. Loading dose with frequent international normalized ratio monitoring could provide sufficient control of anticoagulation.


Assuntos
Anticoagulantes/administração & dosagem , Povo Asiático/genética , Coagulação Sanguínea/genética , Testes Farmacogenômicos/métodos , Vigilância da População , Varfarina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/sangue , Coagulação Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Coeficiente Internacional Normatizado/métodos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Taiwan/epidemiologia , Varfarina/sangue
13.
Neuromolecular Med ; 18(3): 274-82, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27165113

RESUMO

Many population-based epidemiological studies have unveiled an inverse correlation between intake of herbal plants and incidence of stroke. C. nutans is a traditional herbal medicine widely used for snake bite, viral infection and cancer in Asian countries. However, its role in protecting stroke damage remains to be studied. Despite of growing evidence to support epigenetic regulation in the pathogenesis and recovery of stroke, a clear understanding of the underlying molecular mechanisms is still lacking. In the present study, primary cortical neurons were subjected to in vitro oxygen-glucose deprivation (OGD)-reoxygenation and hypoxic neuronal death was used to investigate the interaction between C. nutans and histone deacetylases (HDACs). Using pharmacological agents (HDAC inhibitor/activator), loss-of-function (HDAC siRNA) and gain-of-function (HDAC plasmid) approaches, we demonstrated an early induction of HDAC1/2/3/8 and HDAC6 in neurons after OGD insult. C. nutans extract selectively inhibited HDAC1 and HDAC6 expression and attenuated neuronal death. Results of reporter analysis further revealed that C. nutans suppressed HDAC1 and HDAC6 transcription. Besides ameliorating neuronal death, C. nutans also protected astrocytes and endothelial cells from hypoxic-induced cell death. In summary, results support ability for C. nutans to suppress post-hypoxic HDACs activation and mitigate against OGD-induced neuronal death. This study further opens a new avenue for the use of herbal medicines to regulate epigenetic control of brain injury.


Assuntos
Acanthaceae/química , Hipóxia Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Histona Desacetilase 1/genética , Neurônios/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Células Cultivadas , Medicina Herbária/normas , Desacetilase 6 de Histona/genética , Humanos , Acidente Vascular Cerebral/terapia
14.
Pharmacology ; 98(1-2): 42-50, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27050899

RESUMO

BACKGROUND: Nicorandil, a mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channel opener, exerts protective effects on the cardiovascular system. This study examined the effect of nicorandil on cyclic strain-induced interleukin-8 (IL-8) expression in human umbilical vein endothelial cells (HUVECs). METHODS: Cultured HUVECs were exposed to cyclic strain in the presence or absence of nicorandil (1-10 µmol/l); we then analyzed IL-8 expression. We also assessed the effects of nicorandil on heme oxygenase-1 (HO-1) expression and cyclic strain-modulated IL-8 expression after HO-1 silencing in HUVECs. SUMMARY: HUVECs exposed to cyclic strain showed increased IL-8 messenger RNA expression and protein secretion. Nicorandil (1-10 µmol/l) inhibited cyclic strain-induced IL-8 expression, whereas 5-hydroxydecanoate (100 µmol/l), a selective inhibitor of the mitoKATP channel, completely reversed the inhibitory effects of nicorandil on cyclic strain-induced IL-8 expression. We demonstrated that nicorandil increased HO-1 expression in HUVECs. In addition, cobalt protoporphyrin (10 µmol/l), an inducer of HO-1 expression, mimicked the effects of nicorandil and inhibited IL-8 expression under cyclic strain, whereas zinc protoporphyrin IX (10 µmol/l), an inhibitor of HO-1 expression, antagonized the effect of nicorandil. HO-1 silencing significantly abrogated the inhibitory effects of nicorandil on cyclic strain-induced IL-8 expression, suggesting that HO-1 plays a role in the mechanism of action of nicorandil. KEY MESSAGES: This study is the first to report that nicorandil inhibits cyclic strain-induced IL-8 expression through the induction of HO-1 expression in HUVECs. This finding provides valuable new insight into the molecular pathways contributing to the vasoprotective effects of nicorandil.


Assuntos
Fármacos Cardiovasculares/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Interleucina-8/metabolismo , Nicorandil/farmacologia , Estresse Mecânico , Fenômenos Biomecânicos , Células Cultivadas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Interleucina-8/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética
15.
Am J Chin Med ; 44(2): 377-88, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27080946

RESUMO

Tanshinone IIA is the main effective component of Salvia miltiorrhiza, known as "Danshen," which has been used in many therapeutic remedies in traditional Chinese medicine. However, the direct effects of tanshinone IIA on vascular endothelial cells have not yet been fully described. In the present study, we demonstrated that tanshinone IIA increased heme oxygenase-1 (HO-1) expression in human umbilical vein endothelial cells. Western blot analyses and experiments with specific inhibitors indicated tanshinone IIA enhanced HO-1 expression through the activation of phosphoinositide 3-kinase (PI3K)/Akt and the subsequent induction of nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation. In addition, tanshinone IIA inhibited cyclic strain induced interleukin-8 (IL-8) expression. HO-1 silencing significantly abrogated the repressive effects of tanshinone IIA on strain-induced IL-8 expression, which suggests HO-1 has a role in mediating the effects of tanshinone IIA. This study reports for the first time that tanshinone IIA inhibits cyclic strain-induced IL-8 expression via the induction of HO-1 in endothelial cells, providing valuable new insight into the molecular pathways that may contribute to the effects of tanshinone IIA.


Assuntos
Benzofuranos/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/enzimologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Salvia miltiorrhiza/química , Benzofuranos/isolamento & purificação , Indução Enzimática/efeitos dos fármacos , Inativação Gênica , Heme Oxigenase-1/fisiologia , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo
16.
Sci Rep ; 5: 17007, 2015 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-26582585

RESUMO

Heart failure with preserved ejection fraction (HFPEF) is characterized by myocardial interstitial fibrosis. A total of 146 patients with HFPEF, were recruited. HFPEF severity was determined using Doppler imaging (E/Em) and also cardiac magnetic resonance imaging (CMRI). Canine modeling of HFPEF was induced by aortic banding. Hemodynamic and echocardiographic data were obtained before and after pressure loading and myocardial Galectin-3 was determined. Mechanical stretch of cultured cardiomyocytes served as the cellular model of HFPEF. Patients with severe HFPEF had significantly higher plasma Galectin-3 levels. Significant correlation between plasma Galectin-3 and E/Em in advanced HFPEF patients was noted. After 2 weeks of pressure overload in canine models, the protein expression of Galectin-3 from LV myocardial tissue was significantly increased (p < 0.01) compared with controls. Galectin-3 expression paralleled the severity of LV diastolic dysfunction by evaluation of CMRI (r = -0.58, p = 0.003) and tissue fibrosis (r = 0.59, p = 0.002). After adjusting for confounders for diastolic dysfunction, Galectin-3 levels were still associated with diastolic parameters both in humans (p < 0.001) and canine model (p = 0.041). Mechanical stretch increased Galectin-3 secretion in cultured cardiomyocytes. Both plasma and myocardial Galectin-3 levels correlated with severity of cardiac diastolic dysfunction.


Assuntos
Diástole , Galectina 3/sangue , Coração/fisiopatologia , Índice de Gravidade de Doença , Idoso , Animais , Linhagem Celular , Meios de Contraste , Modelos Animais de Doenças , Cães , Feminino , Fibrose , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Miocárdio/metabolismo , Miocárdio/patologia , Pressão , Ultrassonografia , Função Ventricular Esquerda
17.
Clin Exp Pharmacol Physiol ; 42(6): 632-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25932745

RESUMO

Lycopene is the most potent active antioxidant among the major carotenoids, and its use has been associated with a reduced risk for cardiovascular disease (CVD). Endothelin-1 (ET-1) is a powerful vasopressor synthesized by endothelial cells and plays a crucial role in the pathophysiology of CVD. However, the direct effects of lycopene on vascular endothelial cells have not been fully described. This study investigated the effects of lycopene on cyclic strain-induced ET-1 gene expression in human umbilical vein endothelial cells (HUVECs) and identified the signal transduction pathways that are involved in this process. Cultured HUVECs were exposed to cyclic strain (20% in length, 1 Hz) in the presence or absence of lycopene. Lycopene inhibited strain-induced ET-1 expression through the suppression of reactive oxygen species (ROS) generation through attenuation of p22(phox) mRNA expression and NAD(P)H oxidase activity. Furthermore, lycopene inhibited strain-induced ET-1 secretion by reducing ROS-mediated extrace-llular signal-regulated kinase (ERK) phosphorylation. Conversely, lycopene treatment enhanced heme oxygenase-1 (HO-1) gene expression through the activation of phosphoinositide 3-kinase (PI3K)/Akt pathway, followed by induction of the nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation; in addition, HO-1 silencing partially inhibited the repressive effects of lycopene on strain-induced ET-1 expression. In summary, our study showed, for the first time, that lycopene inhibits cyclic strain-induced ET-1 gene expression through the suppression of ROS generation and induction of HO-1 in HUVECs. Therefore, this study provides new valuable insight into the molecular pathways that may contribute to the proposed beneficial effects of lycopene on the cardiovascular system.


Assuntos
Carotenoides/farmacologia , Endotelina-1/biossíntese , Heme Oxigenase-1/biossíntese , Células Endoteliais da Veia Umbilical Humana/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estresse Mecânico , Células Cultivadas , Relação Dose-Resposta a Droga , Indução Enzimática/efeitos dos fármacos , Indução Enzimática/fisiologia , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Licopeno
18.
Curr Vasc Pharmacol ; 13(1): 54-63, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-23628005

RESUMO

Doxorubicin (DOX) is widely used as an anti-cancer agent although it causes irreversible cardiomyopathy by increasing oxidative stress and deregulating nitric oxide production. Beraprost (BPS), a stable prostacyclin (PGI2) analog, is a potent vasodilator that has beneficial effects on myocardial ischemia. The objectives of the present study were to delineate the uncertain effects of prostcyclin therapy on DOX induced cardiomyopathy and to explore the mechanisms underlying PGI2 and DOX interaction. For this reason, we stimulated endogenous PGI2 production using bicistronic COX-1/PGIS gene transfer and BPS supplementation, and investigated the effects on DOX-induced cardiomyopathy. Caspase-dependent protein content, lactate dehydrogenase (LDH), DNA fragmentation, and TUNEL positive cells were elevated in DOX-treated cardiomyocytes. These indicators were further elevated by adenovirus-COX- 1/PGIS transfection or BPS supplementation. In addition, PGI2 overexpression further increased iNOS expression and superoxide accumulation in cardiomyocytes compared with DOX alone, which may be the reason for aggravated cytotoxicity. Moreover, BPS can induce cAMP response elements (CRE) binding to the iNOS promoter and phospho- cAMP response element binding protein (CREB) expression in a cyclic AMP-dependent manner. Our in vivo studies show that MnTBAP and aminoguanidine treatment of DOX and BPS co-administered in mice can attenuate caspase-3 and PARP-1 protein expression, and improve mouse survival, as observed in the iNOS gene-deleted mice. In conclusion, we demonstrated that BPS or adv-COX-1/PGIS increases PGI2 levels through iNOS expression and peroxynitrite production, via CREB protein phosphorylation; thereby aggravating DOX-mediated cardiotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Epoprostenol/análogos & derivados , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Prostaglandinas/agonistas , Animais , Proteína de Ligação a CREB/metabolismo , Cardiomiopatias/metabolismo , Ciclo-Oxigenase 1/metabolismo , Epoprostenol/metabolismo , Epoprostenol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Isquemia Miocárdica/metabolismo , Ácido Peroxinitroso/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar
19.
Mol Neurobiol ; 51(2): 543-57, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24771044

RESUMO

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor with diverse functions under disease states in multiple cell types. ATF3 has neuroprotective action against cerebral ischemia, which may involve caspase 3. However, the molecular mechanisms underlying ATF3 regulation of apoptosis are largely unknown. Here, we used gain- and loss-of-function and rescue approaches to demonstrate ATF3 attenuating hypoxic neuronal apoptosis. As well, the protective effect of ATF3 was mediated by downregulation of carboxyl-terminal modulator protein (CTMP), a pro-apoptotic factor that inhibits the anti-apoptotic Akt/PKB cascade. ATF3 (1) downregulated the mRNA and protein levels of CTMP; (2) its temporal expression pattern was reciprocal to that of CTMP; and (3) nuclear localization suggested that ATF3 may regulate CTMP transcription following hypoxic insult. Reporter assays demonstrated that ATF3 suppressed CTMP transcription, whereas ATF3 fusion with VP16, converting ATF3 to transcriptional activator, boosted CTMP transcription. By contrast, NF-κB increased CTMP transcription, and degradation-resistant IκBα decreased CTMP transcription. ChIP assays further confirmed that binding of ATF3 to the ATF/CREB site hindered NF-κB binding to the CTMP promoter, which repressed CTMP expression. Furthermore, CTMP siRNA treatment reduced hypoxic neuronal apoptosis by increasing p-Akt (Ser473) levels and leaving the upstream ATF3 level unchanged. We have identified an endogenous neuroprotective ATF3→CTMP signal cascade that may be a therapeutic target for reducing ischemic brain injury.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Apoptose/fisiologia , Isquemia Encefálica/metabolismo , Proteínas de Transporte/metabolismo , Animais , Isquemia Encefálica/prevenção & controle , Proteínas de Transporte/administração & dosagem , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Camundongos , Camundongos Knockout , Palmitoil-CoA Hidrolase
20.
PLoS One ; 9(9): e106812, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25268131

RESUMO

BACKGROUND AND PURPOSE: Regulation of the homeostasis of vascular endothelium is critical for the processes of vascular remodeling and angiogenesis under physiological and pathological conditions. Urotensin II (U-II), a potent vasoactive peptide, participates in vascular and myocardial remodeling after injury. We investigated the protective effect of U-II on doxorubicin (DOX)-induced apoptosis in cultured human umbilical vein endothelial cells (HUVECs) and the potential mechanisms involved in this process. EXPERIMENTAL APPROACH: Cultured HUVECs were treated with vehicle, DOX (1 µM), U-II, or U-II plus DOX. Apoptosis was evaluated by DNA strand break level with TdT-mediated dUTP nick-end labeling (TUNEL) staining. Western blot analysis was employed to determine the related protein expression and flow cytometry assay was used to determine the TUNEL positive cells. KEY RESULTS: U-II reduced the quantity of cleaved caspase-3 and cytosol cytochrome c and increased Bcl-2 expression, which results in protecting HUVECs from DOX-induced apoptosis. U-II induced Activating transcription factor 3 (ATF3) at both mRNA and protein levels in U-II-treated cells. Knockdown of ATF3 with ATF3 siRNA significantly reduced ATF3 protein levels and U-II protective effect under DOX-treated condition. U-II downregulated p53 expression in DOX-induced HUVECs apoptosis, and it rapidly activated extracellular signal-regulated protein kinase (ERK) and Akt. The DOX induced change of p53 was not affected by U-II antagonist (urantide) under ATF-3 knockdown. The inhibitory effect of U-II on DOX-increased apoptosis was attenuated by inhibitors of ERK (U0126) and PI3K/Akt (LY294002). CONCLUSION AND IMPLICATIONS: Our observations provide evidence that U-II protects HUVECs from DOX-induced apoptosis. ERK-Akt phosphorylation, ATF3 activation, and p53 downregulation may play a signal-transduction role in this process.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Urotensinas/fisiologia , Fator 3 Ativador da Transcrição/genética , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Supressora de Tumor p53/metabolismo
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