Background/Aims: Cardiac fibrosis after myocardial infarction (MI) has been identified as a key factor in the development of heart failure, but the mechanisms undelying cardiac fibrosis remained unknown. microRNAs (miRNAs) are novel mechanisms leading to fibrotic diseases, including cardiac fibrosis. Previous studies revealed that miR-22 might be a potential target. However, the roles and mechanisms of miR-22 in cardiac fibrosis remained ill defined. The present study thus addressed the impact of miR-22 in cardiac fibrosis. Methods: After seven days following coronary artery occlusion in mice, tissues used for histology were collected and processed for Masson's Trichrome staining. In addition, cardiac fibroblasts were transfected with mimics and inhibitors of miR-22 using Lipofectamin 2000, and luciferase activity was measured in cell lysates using a luciferase assay kit. Western blotting was used to detect the expression of collagen1, α-SMA and TGFβRI proteins levels, and real time-PCR was employed to measure the Col1α1, Col3α1, miR-22 and TGFβRI mRNA levels. Results: In this study, we found that miR-22 was dynamically downregulated following MI induced by permanent ligation of the left anterior descending coronary artery for 7 days, an effect paralleled by significant collagen deposition. Inhibition of miR-22 with AMO-22 resulted in increased expression of Col1α1, Col3α1 and fibrogenesis in cultured cardiac fibroblasts. Conversely, overexpression of miR-22 in cultured cardiac fibroblasts significantly abrogated angiotensin II-induced collagen formation and fibrogenesis. Furthermore, we found that TGFβRI is a direct target for miR-22, and downregulation of TGFβR may have mediated the antifibrotic effect of miR-22. Conclusion: Our data clearly demonstrate that miR-22 acts as a novel negative regulator of angiotensin II-induced cardiac fibrosis by suppressing the expression of TGFβRI in the heart and may represent a new potential therapeutic target for treating cardiac fibrosis.
In recent studies, the glutamate (Glu) level has been quantified using the modified STEAM sequence on 3T MRI. We enrolled 15 healthy volunteers and a group of 51 patients who experienced stroke for the first time and had a good prognosis. The patients with infarction were divided into three groups according to their scores by using the DSM-IV diagnostic criteria for major depressive disorder and the 17-item Hamilton Depression Rating Scale (HDRS). We studied the association between post-stroke depression and (1)H-MRS measurements in unaffected frontal lobes. Single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) was performed to assess N-acetylaspartate/creatine (NAA)/Cr, (Glu)/Cr, choline (Cho)/Cr, and myoinositol (mI)/Cr ratios in stroke patients. The 11 patients (21.5%) who met the criteria for depression and 9 patients (17.6%) who had a high score for HDRS, (>14) but were not depressed, had a significantly higher Glu/Cr ratio than patients who scored ≤14 on HDRS and control groups (p < 0.001). No differences were found in NAA/Cr, Cho/Cr, or mI/Cr between the groups after stroke. These findings suggest that post-stroke depression is accompanied by changes in glutamate levels in the frontal lobe.
BACKGROUND AND PURPOSE The amelioration of insulin resistance by bilobetin is closely related to its hypolipidaemic effect. The aim of the present study was to determine the insulin‐sensitizing mechanism of bilobetin by elucidating its effect on lipid metabolism. EXPERIMENTAL APPROACH Rats fed a high‐fat diet were treated with bilobetin for either 4 or 14 days before applying a hyperinsulinaemic–euglycaemic clamp. Triglyceride and fatty acids labelled with radioactive isotopes were used to track the transportation and the fate of lipids in tissues. The activity of lipid metabolism‐related enzymes and β‐oxidation rate were measured. Western blot was used to investigate the phosphorylation, translocation and expression of PPARα in several tissues and cultured cells. The location of amino acid residues subjected to phosphorylation in PPARα was also studied. KEY RESULTS Bilobetin ameliorated insulin resistance, increased the hepatic uptake and oxidation of lipids, reduced very‐low‐density lipoprotein triglyceride secretion and blood triglyceride levels, enhanced the expression and activity of enzymes involved in β‐oxidation and attenuated the accumulation of triglycerides and their metabolites in tissues. Bilobetin also increased the phosphorylation, nuclear translocation and activity of PPARα accompanied by elevated cAMP level and PKA activity. Threonine‐129–alanine and/or serine‐163–alanine mutations on the PPARα genes and PKA inhibitors prevented the effects of bilobetin on PPARα. However, cells overexpressing PKA appeared to stimulate the phosphorylation, nuclear translocation and activity of PPARα. CONCLUSIONS AND IMPLICATIONS Bilobetin treatment ameliorates hyperlipidaemia, lipotoxicity and insulin resistance in rats by stimulating PPARα‐mediated lipid catabolism. PKA activation is crucial for this process.
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