Smad2 and Smad3 as mediators of the response of adventitial fibroblasts induced by transforming growth factor β1

Wen

et al. 2016

Sci Rep

The aim of the study was to investigate the role of endogenous sulfur dioxide (SO2)/ aspartate aminotransferase 1 (AAT1) pathway in stretch-induced excessive collagen expression and its mechanism. The mechanical stretch downregulated SO2/AAT1 pathway and increased collagen I and III protein expression. Importantly, AAT1 overexpression blocked the increase in collagen I and III expression, transforming growth factor-β1 (TGF- β1) expression and phosphorylation of Smad2/3 induced by stretch, but AAT1 knockdown mimicked the increase in collagen I and III expression, TGF- β1 expression and phosphorylation of Smad2/3 induced by stretch. Mechanistically, SB431542, a TGF-β1/Smad2/3 inhibitor, eliminated excessive collagen I and III accumulation induced by AAT1 knockdown, stretch or stretch plus AAT1 knockdown. In a rat model of high pulmonary blood flow-induced pulmonary vascular collagen accumulation, AAT1 expression and SO2 content in lung tissues of rat were reduced in shunt rats with high pulmonary blood flow. Supplement of SO2 derivatives inhibited activation of TGF- β1/Smad2/3 pathway and alleviated the excessive collagen accumulation in lung tissues of shunt rats. The results suggested that deficiency of endogenous SO2/AAT1 pathway mediated mechanical stretch-stimulated abnormal collagen accumulation via TGF-β1/Smad2/3 pathway.

Section: Discussionmentioning

confidence: 99%

Mechanical stretching stimulates collagen synthesis via down-regulating SO2/AAT1 pathway

Wen

et al. 2016

Sci Rep

Simvastatin augments activation of liver regeneration through attenuating transforming growth factor‑β1 induced‑apoptosis in obstructive jaundice rats

Fang

Luan

2017

Exp Ther Med

Obstructive jaundice, owing to biliary obstruction, has been illustrated to trigger various biochemical, histological and immunological changes, leading to liver damage or even failure. The detailed molecular mechanism of simvastatin (Sim) involvement in liver regeneration during obstructive jaundice progression remains poorly elucidated. In the present study, an acute obstructive jaundice rat model was established by ligation and division of common bile duct, which was used to investigate the effects of Sim as a hepatoprotective treatment. Male Sprague-Dawley rats were randomly divided into four groups: Sham-operated, bile duct ligation (BDL) plus saline treatment [0.02 mg/kg/d, intraperitoneally (i.p.)], BDL plus low-dose Sim treatment (0.02 mg/kg, i.p.) and BDL plus high-dose Sim treatment (0.2 mg/kg, i.p.). During this experiment, the BDL+normal saline (NS) group demonstrated increased levels of transforming growth factor-β1 (TGF-β1) expression. Furthermore, Sim-treated animals demonstrated significantly downregulated TGF-β1 expression and improved liver function vs. the BDL+NS group, indicating a TGF-β1 antagonizing function. Additionally, Sim increased hepatocyte DNA synthesis in BDL rats compared to both the BDL+NS and Sham group. Apoptosis was increased in BDL+NS compared to the Sham group, and Sim markedly reduced hepatocyte apoptosis in the BDL group. Moreover, analysis of TGF-β1 signaling pathways demonstrated that there was an increased hepatic TGF-β1 and Smad3 expression in the BDL group, which was attenuated in the presence of Sim. In contrast to TGF-β1, Sim induced the activity of the Smad7 (an inhibitor of TGF-β1 signaling) mRNA and Smad7 protein expression. Sim displays hepatoprotective effects in liver cells via the upregulation of Smad7 expression and impaired TGF-β signaling. Furthermore, the observations of the present study may provide evidence on the mechanism behind Sim blunting TGF-β1 signaling, which is used to ameliorate the complication of liver damage and reduce the mortality rates associated with obstructive jaundice.

Erythropoietin Alleviates Burn-induced Muscle Wasting

Tai

et al. 2020

Int. J. Med. Sci.

Background: Burn injury induces long-term skeletal muscle pathology. We hypothesized EPO could attenuate burn-induced muscle fiber atrophy. Methods: Rats were allocated into four groups: a sham burn group, an untreated burn group subjected to third degree hind paw burn, and two burn groups treated with weekly or daily EPO for four weeks. Gastrocnemius muscle was analyzed at four weeks post-burn. Results: EPO attenuated the reduction of mean myofiber cross-sectional area post-burn and the level of the protective effect was no significant difference between two EPO-treated groups (p=0.784). Furthermore, EPO decreased the expression of atrophy-related ubiquitin ligase, atrogin-1, which was up-regulated in response to burn. Compared to untreated burn rats, those receiving weekly or daily EPO groups had less cell apoptosis by TUNEL assay. EPO decreased the expression of cleaved caspase 3 (key factor in the caspase-dependent pathway) and apoptosis-inducing factor (implicated in the caspase-independent pathway) after burn. Furthermore, EPO alleviated connective tissue overproduction following burn via transforming growth factor beta 1-Smad2/3 pathway. Daily EPO group caused significant erythrocytosis compared with untreated burn group but not weekly EPO group. Conclusion: EPO therapy attenuated skeletal muscle apoptosis and fibrosis at four weeks post-burn. Weekly EPO may be a safe and effective option in muscle wasting post-burn.