Galectin-3 Induces Atrial Fibrosis by Activating the TGF-ß1/Smad Pathway in Patients with Atrial Fibrillation.

BACKGROUND: Atrial fibrosis plays a critical role in the occurrence and maintenance of atrial fibrillation. The role of TGF-ß1 in mediating atrial fibrosis is well documented. The ß-galactoside-binding lectin galectin-3 (Gal-3) is mainly produced by macrophages in biological events such as inflammation and angiogenesis. Previous studies have shown that Gal-3 is associated with atrial fibrosis, but the relationship between TGF-ß1 and Gal-3 in atrial fibrosis remains unclear. OBJECTIVE: To determine whether Gal-3 induces atrial fibrosis and atrial fibrillation by activating the TGF-ß1/Smad pathway and whether the expression of Gal-3 is mediated by TGF-ß1, which can enable assessing the relationship between Gal-3 and TGF-ß1 in atrial fibrosis. METHODS: In this study, 30 patients' right atrial appendages were collected and divided into 3 groups: congenital heart disease sinus rhythm group (n = 10, as a control group), rheumatic heart disease sinus rhythm group (n = 10), and rheumatic heart disease atrial fibrillation group (n = 10). Rat atrial fibroblasts were cultured in vitro, and recombinant Gal-3 and recombinant TGF-ß1 proteins were added to the cell culture. The expression of Gal-3, TGF-ß1, Smad2, and collagen I was detected by Western blotting and quantitative real-time PCR. Atrial tissues were stained with Masson's trichrome stain to evaluate the extent of atrial fibrosis. The expression of Gal-3 and TGF-ß1 was detected by immunohistochemical staining and immunofluorescence staining. Gal-3 and TGF-ß1 interaction was demonstrated by immunoprecipitation. RESULTS: The expression levels of Gal-3, TGF-ß1, Smad2, and collagen I were elevated in the rheumatic heart disease atrial fibrillation group compared with the congenital heart disease sinus rhythm group and the rheumatic heart disease sinus rhythm group. In cultured atrial fibroblasts, there is a synergistic interaction between Gal-3 and TGF-ß1. Gal-3 stimulated the TGF-ß1/Smad pathway, and overexpression of TGF-ß1 induced Gal-3 expression. CONCLUSIONS: Gal-3 and TGF-ß1 interact with each other and stimulate the downstream TGF-ß1/Smad pathway. This finding suggests that Gal-3 could be an important factor in TGF-ß1-induced fibrosis in atrial fibrillation.

Potential role of MG53 in the regulation of transforming-growth-factor-ß1-induced atrial fibrosis and vulnerability to atrial fibrillation.

Atrial fibrosis plays a critical role in atrial fibrillation (AF) by the transforming growth factor (TGF)-ß1/Smad pathway. The disordered differentiation, proliferation, migration and collagen deposition of atrial fibroblasts play significant roles in atrial fibrosis. Mitsugumin (MG)53 is predominantly expressed in myocardium of rodents and has multiple biological functions. However, the role of MG53 in cardiac fibrosis remains unclear. This study provided clinical and experimental evidence for the involvement of MG53 in atrial fibrosis in humans and atrial fibrosis phenotype in cultured rat atrial fibroblasts. In atrial tissue from patients we demonstrated that MG53 was expressed in human atrium. Expression of MG53 increased with the extent of atrial fibrosis, which could induce AF. In cultured atrial fibroblasts, depletion of MG53 by siRNA caused down-regulation of the TGF-ß1/Smad pathway, while overexpression of MG53 by adenovirus up-regulated the pathway. MG53 regulated the proliferation and migration of atrial fibroblasts. Besides, exogenous TGF-ß1 suppressed expression of MG53. In conclusion, we demonstrated that MG53 was expressed in human atrium, and may be a potential upstream of the TGF-ß1/Smad pathway in human atrium and rat atrial fibroblasts. This suggests that MG53 is a potential regulator of atrial fibrosis induced by the TGF-ß1/Smad pathway in patients with AF.

The effect of exercise, resveratrol or their combination on Sarcopenia in aged rats via regulation of AMPK/Sirt1 pathway.

Sarcopenia is an age-related syndrome characterized by progressive loss of muscle mass and function. Exercise is an important strategy to prolong life and increase muscle mass, and resveratrol has been shown a variety beneficial effects on skeletal muscle. In the present study, we investigated the potential efficacy of using short-term exercise (six weeks), resveratrol (150mg/kg/day), or combined exercise+resveratrol (150mg/kg/day) on gastrocnemius muscle mass, grip strength, cross-sectional area and microscopic morphology in aged rats, and explored the potential mechanism at the apoptosis level. Six months old SD rats were used as young control group and 24months old SD rats were adopted as aged group. After six weeks intervention, the data provide evidence that exercise, resveratrol or their combination significantly increase the relative grip strength and muscle mass in aged rats (P<0.05). Electron microscopy discovered a significant increase in sarcomere length, I-band and H-zone in aged rats (P<0.05), and exercise, resveratrol or their combination significantly reduced the increasement (P<0.05). Moreover, light microscopy revealed a significant increase on Feret's diameter and cross-sectional area (CSA) in aged rats (P<0.05), but exercise and resveratrol did not show significant effects on them (P>0.05). Furthermore, exercise, resveratrol or their combination significantly increased the expression of p-AMPK and SIRT1, decreased the expression of acetyl P53 and Bax/Bcl-2 ratio in aged rats (P<0.05). These findings show that aged rats show significant changes in gastrocnemius muscle morphology and ultrastructure, and the protective effects of exercise, resveratrol and their combination are probably associated with anti-apoptotic signaling pathways through activation of AMPK/Sirt1.