ABSTRACT
OBJECTIVES: Investigate if azilsartan protects against myocardial hypertrophy by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated pathways. METHODS: Abdominal aortic constriction (AAC)-induced cardiac hypertrophy in rats was applied. Azilsartan or vehicle was administered daily for 6 weeks in sham or AAC rats. Cardiac morphology and ventricular function were determined. Azilsartan effects upon neonatal rat cardiomyocyte (NRCM) hypertrophy and molecular mechanisms were studied in angiotensin (Ang) II-stimulated NRCMs in vitro. Nrf2-small interfering RNA (siRNA) was used to knockdown Nrf2 expression. Messenger RNA (mRNA)/protein expression of Kelch-like erythroid cell-derived protein (Keap)1 and Nrf2 and its downstream antioxidant enzymes was determined by real-time reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. KEY FINDINGS: Azilsartan treatment ameliorated cardiac hypertrophy/fibrosis significantly in AAC rats. Azilsartan increased expression of Nrf2 protein but decreased expression of Keap1 protein. Upregulation of protein expression of Nrf2's downstream antioxidant enzymes by azilsartan treatment was observed. Azilsartan inhibited Ang II-induced NRCM hypertrophy significantly and similar effects on the Keap1-Nrf2 pathway were observed in vivo. Nrf2 knockdown markedly counteracted the beneficial effects of azilsartan on NRCM hypertrophy and the Keap1-Nrf2 pathway. CONCLUSIONS: Azilsartan restrained pressure overload-induced cardiac remodelling by activating the Keap1-Nrf2 pathway and increasing expression of downstream antioxidant enzymes to alleviate oxidative stress.
Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Benzimidazoles/pharmacology , Cardiomegaly/metabolism , Kelch-Like ECH-Associated Protein 1/metabolism , Myocardium/metabolism , NF-E2-Related Factor 2/metabolism , Oxadiazoles/pharmacology , Oxidative Stress/drug effects , Angiotensin II/metabolism , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Cardiomegaly/drug therapy , Female , Heart Ventricles/drug effects , Male , Myocytes, Cardiac/drug effects , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Signal Transduction , Up-RegulationSubject(s)
Tomography, Optical Coherence , Visual Fields , Angiography , Glaucoma , Humans , Nerve Fibers , Optic Disk , Retinal Ganglion Cells , Retinal Vessels , Visual Field TestsABSTRACT
Brain temperature monitoring is important in target temperature management for comatose survivors after cardiac arrest. Since acquisition of brain temperature is invasive and unrealistic in scene of resuscitation, we tried to sought out surrogate sites of temperature measurements that can precisely reflect cerebral temperature. Therefore, we designed this controlled, randomized animal study to investigate whether esophageal temperature can better predict brain temperature in two different hypothermia protocols. The results indicated that esophageal temperature had a stronger correlation with brain temperature in the early phase of hypothermia in both whole and regional body cooling protocols. It means that esophageal temperature was considered as priority method for early monitoring once hypothermia is initiated. This clinical significance of this study is as follows. Since resuscitated patients have unstable hemodynamics, collecting temperature data from esophagus probe is cost-efficient and easier than the catheter in central vein. Moreover, it can prevent the risk of iatrogenic infection comparing with deep vein catheterization, especially in survivors with transient immunoexpressing in hypothermia protocol.
Subject(s)
Body Temperature Regulation/physiology , Body Temperature/physiology , Esophagus/physiology , Animals , Brain , Cardiopulmonary Resuscitation/methods , Coma/physiopathology , Heart Arrest/physiopathology , Hemodynamics/physiology , Hypothermia/physiopathology , SwineABSTRACT
Coronary artery disease is a disease with high morbidity and mortality, in which vascular endothelial dysfunction plays an important role. Hypoxia leads to the inflammation and oxidative stress in endothelial cells, which results in the endothelial injury. The present study was designed to investigate the protective effect and mechanism of folic acid on hypoxia-induced injury in human umbilical vein endothelial cells (HUVEC). Cell counting Kit was used to detect cell survival rate, and apoptotic cells were detected by Hoechst 33258 staining. Intracellular reactive oxygen species (ROS) level was measured using dichloro-dihydro-fluorescein diacetate staining. Western blot was used to determine the protein expressions of extracellular signal protein kinase 1/2 (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2), NOX4 subunit of NAPDH and endothelial nitric oxide synthase (eNOS). Folic acid significantly increased the cell survival rate and decreased the apoptosis of HUVECs treated with folic acid compared with hypoxia-treated HUVEC. Folic acid also decreased ROS level, while it increased the nitrite content in HUVECs. In addition, folic acid decreased protein expressions of NOX4 and p-ERK1/2, while it increased the protein expression of eNOS in HUVECs. Furthermore, N-acetyl cysteine (NAC), the antioxidant, had similar effect on the cell survival rate and the apoptosis. In addition, DPI (NOX4 inhibitor) and U0126 (ERK1/2 inhibitor) rather than NAC decreased the protein expression of NOX4. NAC, DPI, and U0126 increased the protein expression of eNOS. Furthermore, U0126 rather than DPI and NAC decreased the protein expression of p-ERK1/2. Taken together, the results suggested that hypoxia decreased the cell survival rate and induced apoptosis via ERK1/2/NOX4/ROS pathway, which could be the target of folic acid in protecting the HUVECs from injury caused by hypoxia.
