Pub Date : 2022-12-02DOI: 10.2174/1574362418666221202152035
Yinglong Hou, Shenzhou Ma, Ximin Wang, Zhan Li
Heart failure was induced by MI in rats. Two weeks after MI surgery, rats with large infarcts (40%) were randomized into control (untreated MI group, n=10) and IMDtreated (n=10) groups. The MI group and Sham group received saline injections. Rats in the IMD group received IMD1-53, 10nmol/kg/day, intraperitoneally, for four weeks. The AF inducibility and atrial effective refractory period (AERP) were assessed with the electrophysiology test. Additionally, the left atrial diameter and heart function and hemodynamic test were performed. We detected the area changes of myocardial fibrosis in the left atrium by using Masson staining. To detect the protein expression and mRNA expression of transforming growth factor-β1 (TGF-β1), αSMA, collagen Ⅰ, collagen Ⅲ and NADPH oxidase (Nox4) in myocardial fibroblasts and left atrial, we used the Western blot method and the SYBR Green I real-time quantitative polymerase chain reaction (PCR) assay Compared with the MI group, IMD1-53 treatment decreased left atrial diameter and improved cardiac function, and it also improved the left ventricle end-diastolic pressure (LVEDP). IMD1-53 treatment attenuated AERP prolongation and reduced atrial fibrillation inducibility in the IMD group. In vivo, IMD1-53 reduced the left atrial fibrosis content in the heart of MI rats and inhibited mRNA and protein expression of collagen type Ⅰ and Ⅲ. IMD1-53 also inhibited the expression of TGF-β1, α-SMA and Nox4 both in mRNA and protein. In vivo, we found that IMD1-53 inhibited the phosphorylation of Smad3. In vitro, we found that the down-regulation of the expression of Nox4 was partly dependent on the TGF-β1/ALK5 pathway. IMD1-53 reduced the inducibility and duration of AF and atrial fibrosis in the rats after the MI operation. The possible mechanisms are associated with the inhibition of TGFβ1/Smad3-related fibrosis and TGF-β1/Nox4 activity. Therefore, IMD1-53 may be a promising agent as upstream therapy for the prevention of AF. Compared with the MI group, IMD1-53 treatment decreased left atrial diameter and improved cardiac function, it also improved the left ventrical end diastolic pressure (LVEDP). IMD1-53 treatment attenuated AERP prolongation and reduced atrial fibrillation inducibility in the IMD group. In vivo, the results showed that IMD1-53 reduced the left atrial fibrosis content on the heart of MI rats and inhibited the expression of collagen type Ⅰ and Ⅲ both in mRNA and protein. IMD1-53 also inhibited the expression of TGF-β1, α-SMA and Nox4 both in mRNA and protein. In vivo, the study also showed that IMD1-53 inhibited the phosphorylation of Smad3. In vitro, we found that the down-regulated the expression of Nox4 was partly dependent on TGF-β1/ALK5 pathway. none.
心肌梗死引起大鼠心力衰竭。心肌梗死术后2周,大面积梗死(40%)大鼠随机分为对照组(未治疗心肌梗死组,n=10)和imd治疗组(n=10)。心肌梗死组和假手术组均给予生理盐水注射。imd组大鼠给予IMD1-53, 10nmol/kg/天,腹腔注射,连续4周。电生理试验评估心房颤动诱导能力和心房有效不应期(AERP)。同时进行左房内径、心功能及血流动力学检查。用马松染色法检测左心房心肌纤维化面积变化。为了检测心肌成纤维细胞和左心房中转化生长因子-β1 (TGF-β1)、αSMA、胶原Ⅰ、胶原Ⅲ和NADPH氧化酶(Nox4)的蛋白表达和mRNA表达,我们采用Western blot法和SYBR Green I实时定量聚合酶链反应(PCR)检测。与MI组比较,IMD1-53治疗可降低左心房内径,改善心功能,改善左心室舒张末压(LVEDP)。IMD1-53治疗减少了imd组的AERP延长和降低了心房颤动的诱发性。体内IMD1-53降低心肌梗死大鼠心脏左心房纤维化含量,抑制胶原型Ⅰ和ⅢmRNA和蛋白表达。IMD1-53对TGF-β1、α-SMA和Nox4的mRNA和蛋白表达均有抑制作用。在体内,我们发现imd1 -53抑制Smad3的磷酸化。在体外,我们发现Nox4表达的下调部分依赖于TGF-β1/ALK5通路。IMD1-53降低心肌梗死术后大鼠房颤和心房纤维化的诱发性和持续时间。其可能机制与抑制TGF-β1/ smad3相关纤维化和TGF-β1/Nox4活性有关。因此,IMD1-53可能是预防房颤上游治疗的有希望的药物。与MI组相比,IMD1-53治疗可减小左房内径,改善心功能,并改善左室舒张末期压(LVEDP)。IMD1-53治疗减少了IMD组的AERP延长,降低了心房颤动的诱发性。体内实验结果显示,IMD1-53降低心肌梗死大鼠心脏左心房纤维化含量,抑制胶原型Ⅰ和ⅢmRNA和蛋白的表达。IMD1-53对TGF-β1、α-SMA和Nox4的mRNA和蛋白表达均有抑制作用。在体内,该研究还表明IMD1-53抑制Smad3的磷酸化。在体外,我们发现Nox4的表达下调部分依赖于TGF-β1/ALK5通路。
{"title":"Intermedin 1-53 Ameliorates Atrial Fibrosis and Reduces Inducibility of\u0000Atrial Fibrillation via TGF-β1/pSmad3 and Nox4 Pathways in a Rat Model\u0000of Heart Failure","authors":"Yinglong Hou, Shenzhou Ma, Ximin Wang, Zhan Li","doi":"10.2174/1574362418666221202152035","DOIUrl":"https://doi.org/10.2174/1574362418666221202152035","url":null,"abstract":"\u0000\u0000Heart failure was induced by MI in rats. Two weeks after MI surgery, rats\u0000with large infarcts (40%) were randomized into control (untreated MI group, n=10) and IMDtreated (n=10) groups. The MI group and Sham group received saline injections. Rats in the IMD\u0000group received IMD1-53, 10nmol/kg/day, intraperitoneally, for four weeks. The AF inducibility\u0000and atrial effective refractory period (AERP) were assessed with the electrophysiology test. Additionally, the left atrial diameter and heart function and hemodynamic test were performed. We detected the area changes of myocardial fibrosis in the left atrium by using Masson staining. To detect the protein expression and mRNA expression of transforming growth factor-β1 (TGF-β1), αSMA, collagen Ⅰ, collagen Ⅲ and NADPH oxidase (Nox4) in myocardial fibroblasts and left atrial,\u0000we used the Western blot method and the SYBR Green I real-time quantitative polymerase chain\u0000reaction (PCR) assay\u0000\u0000\u0000\u0000Compared with the MI group, IMD1-53 treatment decreased left atrial diameter and improved cardiac function, and it also improved the left ventricle end-diastolic pressure (LVEDP).\u0000IMD1-53 treatment attenuated AERP prolongation and reduced atrial fibrillation inducibility in the\u0000IMD group. In vivo, IMD1-53 reduced the left atrial fibrosis content in the heart of MI rats and inhibited mRNA and protein expression of collagen type Ⅰ and Ⅲ. IMD1-53 also inhibited the expression of TGF-β1, α-SMA and Nox4 both in mRNA and protein. In vivo, we found that IMD1-53\u0000inhibited the phosphorylation of Smad3. In vitro, we found that the down-regulation of the expression of Nox4 was partly dependent on the TGF-β1/ALK5 pathway.\u0000\u0000\u0000\u0000IMD1-53 reduced the inducibility and duration of AF and atrial fibrosis in the rats\u0000after the MI operation. The possible mechanisms are associated with the inhibition of TGFβ1/Smad3-related fibrosis and TGF-β1/Nox4 activity. Therefore, IMD1-53 may be a promising\u0000agent as upstream therapy for the prevention of AF.\u0000\u0000\u0000\u0000Compared with the MI group, IMD1-53 treatment decreased left atrial diameter and improved cardiac function, it also improved the left ventrical end diastolic pressure (LVEDP). IMD1-53 treatment attenuated AERP prolongation and reduced atrial fibrillation inducibility in the IMD group. In vivo, the results showed that IMD1-53 reduced the left atrial fibrosis content on the heart of MI rats and inhibited the expression of collagen type Ⅰ and Ⅲ both in mRNA and protein. IMD1-53 also inhibited the expression of TGF-β1, α-SMA and Nox4 both in mRNA and protein. In vivo, the study also showed that IMD1-53 inhibited the phosphorylation of Smad3. In vitro, we found that the down-regulated the expression of Nox4 was partly dependent on TGF-β1/ALK5 pathway.\u0000\u0000\u0000\u0000none.\u0000","PeriodicalId":10868,"journal":{"name":"Current Signal Transduction Therapy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42431913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}