Xue-Liang Zhou1, Yi-Hu Fang1, Li Wan1, Qi-Rong Xu1, Huang Huang1, Rong-Rong Zhu2, Qi-Cai Wu1, Ji-Chun Liu1. 1. Department of Cardiac Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, China. 2. Department of Obstetrics and Gynecology, Jiangxi Province Hospital of Integrated Traditional Chinese and Western Medicine, China.
Abstract
PURPOSE: During myocardial infarction (MI), cardiac fibroblasts (CFs) transform into myofibroblast (CMT). This study aimed to investigate the crosstalk of Notch1 and transforming growth factor-β1 (TGF-β1)/Smad3 signaling in the regulation of CMT and myocardial fibrosis. METHODS: Primary CFs were isolated from young rats and treated with TGF-β1 or adenovirus to overexpress or knockdown Notch1 intracellular domain (N1ICD) or Smad3. RESULTS: TGF-β1 decreased the expression of fibroblast markers but increased the expression of myofibroblast markers in rat CFs. TGF-β1 increased the proliferation, invasion, and adhesion, and the secretion of collagen I of CFs, and these effects were inhibited by N1ICD overexpression. Moreover, endogenous Smad3 phosphorylation in CFs was enhanced by N1ICD knockdown, whereas TGF-β1 induced Smad3 phosphorylation was antagonized by the N1ICD overexpression. Conversely, endogenous N1ICD activation in CFs was antagonized by Smad3, whereas TGF-β1 induced N1ICD inactivation was antagonized by Smad3 knockdown. Coimmunoprecipitation showed that N1ICD interacted with Smad3 and immunostaining revealed the colocalization of N1ICD and Smad3 in the nuclei of CFs. Moreover, we demonstrated the functional antagonism of N1ICD and Smad3 on the phenotypes of CFs. Finally, TGF-β1/Smad3 signaling promoted whereas Notch signaling inhibited myocardial fibrosis in rat MI model. CONCLUSION: Notch signaling inhibits CMT by antagonizing TGF-β1/Smad3 signaling. Notch signaling activators and TGF-β1/Smad3 signaling inhibitors could be exploited for therapeutic intervention to inhibit myocardial fibrosis after MI.
PURPOSE: During myocardial infarction (MI), cardiac fibroblasts (CFs) transform into myofibroblast (CMT). This study aimed to investigate the crosstalk of Notch1 and transforming growth factor-β1 (TGF-β1)/Smad3 signaling in the regulation of CMT and myocardial fibrosis. METHODS: Primary CFs were isolated from young rats and treated with TGF-β1 or adenovirus to overexpress or knockdown Notch1 intracellular domain (N1ICD) or Smad3. RESULTS: TGF-β1 decreased the expression of fibroblast markers but increased the expression of myofibroblast markers in rat CFs. TGF-β1 increased the proliferation, invasion, and adhesion, and the secretion of collagen I of CFs, and these effects were inhibited by N1ICD overexpression. Moreover, endogenous Smad3 phosphorylation in CFs was enhanced by N1ICD knockdown, whereas TGF-β1 induced Smad3 phosphorylation was antagonized by the N1ICD overexpression. Conversely, endogenous N1ICD activation in CFs was antagonized by Smad3, whereas TGF-β1 induced N1ICD inactivation was antagonized by Smad3 knockdown. Coimmunoprecipitation showed that N1ICD interacted with Smad3 and immunostaining revealed the colocalization of N1ICD and Smad3 in the nuclei of CFs. Moreover, we demonstrated the functional antagonism of N1ICD and Smad3 on the phenotypes of CFs. Finally, TGF-β1/Smad3 signaling promoted whereas Notch signaling inhibited myocardial fibrosis in rat MI model. CONCLUSION:Notch signaling inhibits CMT by antagonizing TGF-β1/Smad3 signaling. Notch signaling activators and TGF-β1/Smad3 signaling inhibitors could be exploited for therapeutic intervention to inhibit myocardial fibrosis after MI.
Authors: Jesse D Rogers; Brian A Aguado; Kelsey M Watts; Kristi S Anseth; William J Richardson Journal: Proc Natl Acad Sci U S A Date: 2022-02-22 Impact factor: 12.779
Authors: Victor Camberos; Jonathan Baio; Ana Mandujano; Aida F Martinez; Leonard Bailey; Nahidh Hasaniya; Mary Kearns-Jonker Journal: Int J Mol Sci Date: 2021-03-30 Impact factor: 5.923