RESUMO
Inflammation and reactive oxygen species (ROS) are important factors in the pathogenesis of atherosclerosis (AS). 5,2'-dibromo-2,4',5'-trihydroxydiphenylmethanone (TDD), possess anti-atherogenic properties; however, its underlying mechanism of action remains unclear. Therefore, we sought to understand the therapeutic molecular mechanism of TDD in inflammatory response and oxidative stress in EA.hy926 cells. Microarray analysis revealed that the expression of homeobox containing 1 (HMBOX1) was dramatically upregulated in TDD-treated EA.hy926 cells. According to the gene ontology (GO) analysis of microarray data, TDD significantly influenced the response to lipopolysaccharide (LPS); it suppressed the LPS-induced adhesion of monocytes to EA.hy926 cells. Simultaneously, TDD dose-dependently inhibited the production or expression of IL-6, IL-1ß, MCP-1, TNF-α, VCAM-1, ICAM-1 and E-selectin as well as ROS in LPS-stimulated EA.hy926 cells. HMBOX1 knockdown using RNA interference attenuated the anti-inflammatory and anti-oxidative effects of TDD. Furthermore, TDD inhibited LPS-induced NF-κB and MAPK activation in EA.hy926 cells, but this effect was abolished by HMBOX1 knockdown. Overall, these results demonstrate that TDD activates HMBOX1, which is an inducible protective mechanism that inhibits LPS-induced inflammation and ROS production in EA.hy926 cells by the subsequent inhibition of redox-sensitive NF-κB and MAPK activation. Our study suggested that TDD may be a potential novel agent for treating endothelial cells dysfunction in AS.
Assuntos
Anti-Inflamatórios/farmacologia , Proteínas de Homeodomínio/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Aterosclerose/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Activating IK1 channels is considered to be a promising antiarrhythmic strategy. Zacopride has been identified as a selective IK1 channel agonist and can suppress triggered arrhythmias. Whether this drug also exerts a beneficial effect on cardiac remodeling is unknown, and the present study sought to address this question. Cardiac remodeling was induced through coronary ligation-induced myocardial infarction (MI) in male Sprague-Dawley rats. Zacopride (15 µg/kg) was administered (intraperitoneally) daily for 28 days after MI to determine whether it could attenuate MI-induced cardiac remodeling. A 4-week treatment with zacopride attenuated post-MI cardiac remodeling, as shown by the reduced left ventricular end-diastolic dimension and left ventricular end-systolic dimension and the increased ejection fraction and fractional shortening in zacopride-treated animals compared with animals treated with vehicle (all P < 0.05). Furthermore, zacopride significantly decreased myocardial collagen deposition, cardiomyocyte hypertrophy, the plasma level of brain natriuretic peptide, and cardiomyocyte ultrastructural injury. Zacopride also upregulated the expression of the IK1 channel protein and downregulated the expression of phosphorylated p70S6 kinase (p-p70S6K) and mTOR. These beneficial effects of zacopride were partially abolished by the IK1 channel blocker chloroquine. We conclude that the activation of IK1 channel by zacopride attenuates post-MI cardiac remodeling by suppressing mTOR-p70S6 kinase signaling.
Assuntos
Antiarrítmicos/uso terapêutico , Benzamidas/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Canais de Potássio Corretores do Fluxo de Internalização/agonistas , Remodelação Ventricular/efeitos dos fármacos , Animais , Antiarrítmicos/administração & dosagem , Benzamidas/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Cloroquina/sangue , Cloroquina/farmacologia , Ecocardiografia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/ultraestrutura , Masculino , Microscopia Eletrônica de Transmissão , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/ultraestrutura , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Ratos Sprague-DawleyRESUMO
The vascular endothelium is important in the physiological homeostasis of blood vessels. Increasing evidence demonstrates that oxidative stressinduced endothelial damage is involved in the pathogenesis of several cardiovascular diseases, including atherosclerosis. Hyperoside, one of major active components from Apocynum venetum L. (LuoBuMa), which is a traditional Chinese herbal medicine commonly used for the prevention of cardiovascular diseases, exhibits diverse bioactivities, including antiinflammatory and antioxidant effects. In the present study, the protective effects of hyperoside against hydrogen peroxide (H2O2)induced apoptosis of human umbilical vein endothelial cells (HUVECs) were investigated. The results demonstrated that hyperoside significantly prevented the loss of cell viability, the increase of endothelial Ca2+ content and apoptosis in H2O2induced HUVECs. Additionally, reverse transcription-polymerase chain reaction and western blot analysis revealed that hyperoside significantly decreased the mRNA expression levels of Bcell lymphoma (Bcl)2 associated X protein (Bax), cleaved caspase3 and phosphorylatedp38, while increasing the mRNA expression of Bcl2 in H2O2induced HUVECs. The present findings suggested that hyperoside has protective effects against H2O2induced apoptosis in HUVECs and serves a key role in the prevention of cardiovascular diseases.