RESUMEN
Latest clinical research shows that trimetazidine therapy during the perioperative period relieves endothelial dysfunction in patients with unstable angina induced by percutaneous coronary intervention. In this study we investigated the effects of TMZ on myocardial angiogenesis in pressure overload-induced cardiac hypertrophy mice. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery. TAC mice were administered trimetazidine (2.8 mg/100 µL, i.g.) for 28 consecutive days. We showed that trimetazidine administration significantly increased blood vessel density in the left ventricular myocardium and abrogated cardiac dysfunction in TAC mice. Co-administration of a specific HSF1 inhibitor KRIBB11 (1.25 mg/100 µL, i.h.) abrogated the angiogenesis-promoting effects of trimetazidine in TAC mice. Using luciferase reporter and electrophoretic mobility shift assays we demonstrated that the transcription factor HSF1 bound to the promoter region of VEGF-A, and the transcriptional activity of HSF1 was enhanced upon trimetazidine treatment. In molecular docking analysis we found that trimetazidine directly bound to Akt via a hydrogen bond with Asp292 and a pi-pi bond with Trp80. In norepinephrine-treated HUVECs, we showed that trimetazidine significantly increased the phosphorylation of Akt and the synergistic nuclear translocation of Akt and HSF1, as well as the binding of Akt and HSF1 in the nucleus. These results suggest that trimetazidine enhances myocardial angiogenesis through a direct interaction with Akt and promotion of nuclear translocation of HSF1, and that trimetazidine may be used for the treatment of myocardial angiogenic disorders in hypertensive patients.
Asunto(s)
Trimetazidina , Animales , Ratones , Inductores de la Angiogénesis/farmacología , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Factores de Transcripción del Choque Térmico/metabolismo , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Miocardio/metabolismo , Miocitos Cardíacos , Neovascularización Patológica/metabolismo , Norepinefrina/metabolismo , Norepinefrina/farmacología , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de Transcripción/metabolismo , Trimetazidina/metabolismo , Trimetazidina/farmacología , Trimetazidina/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoAsunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Biomarcadores/metabolismo , Enfermedad de Crohn/diagnóstico , Mucosa Intestinal/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Estudios de Casos y Controles , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Homólogo 1 de la Proteína Discs Large , Humanos , Mucosa Intestinal/patología , Proteínas de la Membrana/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
Myostatin, a member of the TGF-beta family, negatively regulates skeletal muscle development. Mutation of myostatin activity leads to increases muscle growth and carcass lean yield. The bovine myostatin mutation cDNA was amplified by polymerase chain reaction, and then sub-cloned into the expression vector pET-30a( + ) to form the expression plasmid pET30a (+)-action/ Myostatin. The recombinant plasmid was transformed into E. coli BL21. The overexpression product of pET30a (+)-action/ Myostatin was been showed in vitro. Sheep skeletal muscle cell were cultured with the purified myostatin mutation C-terminal peptide. The results of this study suggest that had a powerful activity to stimulate the hyperplasia and proliferation of sheep muscle cells and shows high biochemical activity.