RESUMO
The present study compared the effects of resveratrol and its dimer ε-viniferin on vascular endothelial cells (VECs) functions, and on the blood pressure and cardiac mass of spontaneously hypertensive rats (SHRs). Treatment of VECs with these compounds enhanced cell proliferation via nitric oxide generation and protected the cells from oxidative stress by suppressing increases in intracellular oxygen species. ε-Viniferin was more potent than resveratrol in most of these effects. ε-Viniferin, but not resveratrol inhibited angiotensin-converting enzyme activity in vitro. Three weeks of ε-viniferin treatment (5 mg/kg) reduced the systolic blood pressure and improved the whole cardiac mass and left ventricle mass indexes in SHRs. In contrast, resveratrol administration (2.5 mg/kg) failed to lower the blood pressure and significantly improve these mass indexes. These data suggest that ε-viniferin as well as resveratrol may be involved in protecting the functions of VECs and the heart.
Assuntos
Antioxidantes/farmacologia , Benzofuranos/farmacologia , Células Endoteliais/efeitos dos fármacos , Miocárdio/patologia , Estilbenos/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Masculino , Óxido Nítrico/biossíntese , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Espécies Reativas de Oxigênio/antagonistas & inibidores , Resveratrol , SuínosRESUMO
Resveratrol is a strong candidate for explaining an irreversible correlation between red wine consumption and coronary heart disease. The present study examined the effect of ε-viniferin, a dehydrodimer of resveratrol, on vascular smooth muscle cells (VSMCs), because ε-viniferin functions are poorly understood in spite of its comparable content to resveratrol in red wines and grapes. Both ε-viniferin and resveratrol inhibited platelet-derived growth factor-induced cell proliferation, migration, and reactive oxygen species (ROS) production, in addition to inducing nitric oxide generation. ε-Viniferin was more effective than resveratrol in these effects, except for inhibiting ROS production. The compounds also increased the expression of the antioxidant enzyme, hemeoxygenase-1, via transcription factor Nrf2. The phosphatidylinositol 3-kinase-Akt pathway was implicated in resveratrol-dependent nuclear Nrf2 accumulation, whereas extracellular signal-regulated kinase and p38 were involved in ε-viniferin-induced Nrf2 accumulation. These data suggest that ε-viniferin may function more effectively than resveratrol in different mechanisms and cooperatively with resveratrol in preventing atherosclerosis.
Assuntos
Benzofuranos/farmacologia , Movimento Celular/efeitos dos fármacos , Heme Oxigenase-1/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Estilbenos/farmacologia , Vinho , Animais , Aterosclerose/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Heme Oxigenase-1/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Resveratrol , Estilbenos/química , Vinho/análise , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
This study investigated the atheroprotective properties of olive oil polyphenol, hydroxytyrosol (HT), in combination with carbon monoxide-releasing molecule-2 (CORM-2) that acts as a carbon monoxide donor using vascular endothelial cells (VECs). Our results showed that CORM-2 could strengthen the cytoprotective and anti-apoptotic effects of HT against TNFα-induced cellular damage by enhancing cell survival and the suppression of caspase-3 activation. While HT alone attenuated NFκBp65 phosphorylation and IκBα degradation triggered by TNFα in a dose-dependent manner, combined treatment of HT with CORM-2 but not iCORM-2 nearly completely blocked these TNFα effects. Furthermore, combined action of both compounds results in the inhibition of NFκB nuclear translocation. Results also indicate that both compounds time-dependently increased eNOS phosphorylation levels and the combination of HT with CORM-2 was more effective in enhancing eNOS activation and NO production in VECs. The NOS inhibitor, L-NMMA, significantly suppressed the combined effects of HT and CORM-2 on TNFα-triggered NFκBp65 and IκBα phosphorylation as well as decreased cell viability. Together, these data suggest that carbon monoxide-dependent regulation of NO production by the combination of HT with CORM-2 may provide a therapeutic benefit in the treatment of endothelial dysfunction and atherosclerosis.
Assuntos
Células Endoteliais/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Álcool Feniletílico/análogos & derivados , Fator de Necrose Tumoral alfa/metabolismo , Animais , Apoptose/efeitos dos fármacos , Monóxido de Carbono/metabolismo , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Azeite de Oliva , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Fosforilação/efeitos dos fármacos , Óleos de Plantas/química , Suínos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genéticaRESUMO
AIMS: Indoxyl sulfate, a uremic toxin, is considered a risk factor for arteriosclerosis in patients with chronic kidney disease (CKD). We previously reported the actions of indoxyl sulfate including crosstalk with platelet-derived growth factor (PDGF) signaling in vascular smooth muscle cells (VSMCs). The present study examines whether indoxyl sulfate enhances angiotensin II (Ang II) signaling because serum levels of Ang II are elevated in patients with CKD. MAIN METHODS: The effect of indoxyl sulfate and Ang II on phosphorylation of ERK and epidermal growth factor receptor (EGFR), and migration were determined using VSMCs. The expression of EGFR was determined using not only VSMCs but also artery of normal, uremic, and indoxyl sulfate-administrated uremic rats. KEY FINDINGS: Ang II-dependent phosphorylation of ERK and EGFR, and migration of VSMCs were augmented by a prior 24-h incubation with indoxyl sulfate even in the absence of indoxyl sulfate during Ang II stimulation. The expression of EGFR was increased in indoxyl sulfate-stimulated cultured VSMCs. In arterial VSMCs of rats, serum levels of indoxyl sulfate reflected the expression level of EGFR. The upregulated EGFR expression by indoxyl sulfate was suppressed by the antioxidant, N-acetylcysteine. An EGFR inhibitor, AG1478, repressed the enhancement of Ang II-induced cellular effects by indoxyl sulfate. Taken together, these findings indicate that indoxyl sulfate enhances Ang II signaling through reactive oxygen species-induced EGFR expression. SIGNIFICANCE: The actions of indoxyl sulfate including crosstalk with Ang II signaling may be closely involved in the pathogenesis of CKD associated with arteriosclerosis.