RESUMO
Increase of myocardial oxidative stress is closely related to the occurrence and development of cardiac hypertrophy. Cordycepin, also known as 3'-deoxyadenosine, is a natural bioactive substance extracted from Cordyceps militaris (which is widely cultivated for commercial use in functional foods and medicine). Since cordycepin suppresses oxidative stress both in vitro and in vivo, we hypothesized that cordycepin would inhibit cardiac hypertrophy by blocking oxidative stress-dependent related signalling. In our study, a mouse model of cardiac hypertrophy was induced by aortic banding (AB) surgery. Mice were intraperitoneally injected with cordycepin (20 mg/kg/d) or the same volume of vehicle 3 days after-surgery for 4 weeks. Our data demonstrated that cordycepin prevented cardiac hypertrophy induced by AB, as assessed by haemodynamic parameters analysis and echocardiographic, histological and molecular analyses. Oxidative stress was estimated by detecting superoxide generation, superoxide dismutase (SOD) activity and malondialdehyde levels, and by detecting the protein levels of gp91phox and SOD. Mechanistically, we found that cordycepin activated activated protein kinase α (AMPKα) signalling and attenuated oxidative stress both in vivo in cordycepin-treated mice and in vitro in cordycepin treated cardiomyocytes. Taken together, the results suggest that cordycepin protects against post-AB cardiac hypertrophy through activation of the AMPKα pathway, which subsequently attenuates oxidative stress.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Cardiomegalia/tratamento farmacológico , Desoxiadenosinas/uso terapêutico , Transdução de Sinais , Angiotensina II/farmacologia , Animais , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Desoxiadenosinas/farmacologia , Fibrose , Hemodinâmica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Pressão , Transdução de Sinais/efeitos dos fármacosRESUMO
Cell apoptosis induced by Angiotensin II (Ang II) has a critical role in the development of cardiovascular diseases. The aim of the present study was to investigate whether sanguinarine (SAN), a drug which was proved to have antioxidant, antiproliferative and immune enhancing effects, can abolish cell apoptosis induced by Ang II. In the present study, H9c2 cardiac cells were stimulated with 10 µM Ang II with or without SAN. The level of intracellular reactive oxygen species (ROS) generation was assessed using dichlorodihydrofluorescein diacetate, and changes of the mitochondrial membrane potential (MMP) were assessed using JC1 staining. Furthermore, mRNA expression of NOX2 was determined by reverse transcription quantitative polymerase chain reaction, and apoptosis was detected by Annexin V/propidium iodide staining and flow cytometry. The expression of Bcell lymphoma 2 (Bcl2), Bcl2associated X protein (Bax) as well as cleaved (c)caspase 3 and 9 were detected by western blot analysis, and the activity of caspase 3 and 9 was detected using an ELISA. The results of the present study showed that NOX2 expression and ROS generation induced by Ang II were inhibited by SAN, and the Ang 2induced MMP loss was also ameliorated. Furthermore, Ang IIinduced H9c2 cardiac cell apoptosis as well as ccaspase 3 and 9 levels were significantly reduced by SAN. Investigation of the possible pathway involved in the antiapoptotic effect of SAN showed that the expression of Bcl2 was decreased, while that of Bax was increased following stimulation with Ang II, which was reversed following treatment with SAN. In addition, Ang II enhanced the activity of caspase 9 and cleaved downstream caspases such as caspase3, initiating the caspase cascade, while pretreatment of H9c2 cardiac cells with SAN blocked these effects. In conclusion, the findings of the present study indicated that SAN inhibits the apoptosis of H9c2 cardiac cells induced by Ang II, most likely via restoring ROSmediated decreases of the MMP.