文献类型：期刊文献

英文题名：mTORC1 is a key regulator that mediates OGD- and TGFβ1-induced myofibroblast transformation and chondroitin-4-sulfate expression in cardiac fibroblasts

作者：Li, Chao[1,2];Zhang, Zheng[1,3,6];Peng, Yu[2,3];Zhang, Yanying[4];Kang, Wanrong[4];Li, Yingdong[5];Hai, Yang[4]

第一作者：Li, Chao

通信作者：Zhang, Z[1]

机构：[1]Lanzhou Univ, Clin Coll 1, Lanzhou, Peoples R China;[2]Lanzhou Univ, Gansu Key Lab Cardiovasc Dis, Hosp 1, Lanzhou, Peoples R China;[3]Lanzhou Univ, Dept Cardiol, Hosp 1, Lanzhou, Peoples R China;[4]Gansu Univ Chinese Med, Res Expt Ctr, Lanzhou, Peoples R China;[5]Gansu Univ Chinese Med, Key Lab Prevent & Treatment Chron Dis, Tradit Chinese Med Gansu Prov, Lanzhou 730000, Gansu, Peoples R China;[6]Lanzhou Univ, Dept Cardiol, Hosp 1, 1 Donggang West Rd, Lanzhou 730000, Gansu, Peoples R China

第一机构：Lanzhou Univ, Clin Coll 1, Lanzhou, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Dept Cardiol, Hosp 1, 1 Donggang West Rd, Lanzhou 730000, Gansu, Peoples R China.

年份：2022

卷号：23

期号：6

外文期刊名：EXPERIMENTAL AND THERAPEUTIC MEDICINE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000798275200001)】；

语种：英文

外文关键词：chondroitin sulfate proteoglycans; chondroitin-4-sulfate; Smad3; mTORC1; cardiac fibroblasts

摘要：Ischemia-reperfusion infarct-derived chondroitin sulfate proteoglycans (CSPGs) are important for sustaining denervation of the infarct. Sympathetic denervation within the heart after myocardial infarction (MI) predicts the probability of a higher risk for serious ventricular arrhythmias. Chondroitin-4-sulfate (C4S) is the predominant chondroitin sulfate component in the heart. However, the mechanisms that induce CSPG expression in fibroblasts following MI remain to be elucidated. The present study found that oxygen-glucose deprivation (OGD) and TGF beta 1 stimulation induced myofibroblast transformation and C4S synthesis in vitro by using reverse transcription-quantitative PCR, western blotting and immunofluorescence. MTT assay was used to detect cell viability following OGD or OGD + TGF lotreatment. Using the PI3K inhibitor ZSTK474, the Akt inhibitor MK2206, or the mTOR inhibitor AZD8055, it was observed that OGD and TGF beta 1 stimulation induced myofibroblast transformation and that C4S synthesis was mTOR-dependent, whereas the upstream canonical PI3K/Akt axis was dispensable by using western blotting and immunofluorescence. siRNA knockdown of Smad3, Raptor, or Rictor, indicated that mTORC1 was critical for promoting OGD- and TGF beta 1-induced myofibroblast transformation and C4S synthesis by using western blotting and immunofluorescence. This response, may be mediated via cooperation between canonical Smad3 and mTORC1 signaling. These data suggested that inhibiting myofibroblast transformation may reduce C4S synthesis. Target mTORC1 may provide additional insight into the regeneration of sympathetic nerves and the reduction of fibrosis after MI at the cellular level. These findings may contribute to the understanding of the mechanism by which C4S overproduction in the hearts of patients with MI is associated with myocardial fibrosis.