期刊
OPEN MEDICINE
卷 17, 期 1, 页码 463-474出版社
DE GRUYTER POLAND SP Z O O
DOI: 10.1515/med-2022-0432
关键词
gap junction; connexin43; TGF beta1; mechanical stretch; actin
资金
- Medical Research Foundation of Oregon [GCAEI0532A]
- OHSU Faculty Initiative Pool fund
- Oregon Clinical and Translational Research Institute (OCTRI) [UL1TR002369]
- National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH) [UL1TR002369]
- NIH Road map for Medical Research
This study found that mechanical stretch increases Cx43 protein expression in human umbilical vein endothelial cells, mainly through the TGF beta1 receptor signaling pathway and involving the actin and microtubule cytoskeletal network.
Many physiological and pathophysiological processes in cells or tissues are involved in mechanical stretch, which induces the gap junction gene expression and cytokine TGF beta changes. However, the underlying mechanisms of the gap junction gene expression remain unknown. Here, we showed that the mRNA and protein levels of Cx43 in human umbilical vein endothelial cells (HUVECs) were significantly increased after 24 h stretch stimulation, and TGF beta1 (not TGF beta2) expression was also upregulated. Administration of TGF beta1 into HUVECs without stretch also induced upregulation of Cx43 expression. However, SB431542, a specific inhibitor of the TGF beta1 receptor, blocked the Cx43 protein upregulation caused by TGF beta1. Further, the increase of Cx43 protein expression under the stretch condition was partially blocked by SB431542; it was also partially blocked by simultaneous administration of anti-TGF beta1 monoclonal neutralization antibody. Importantly, the upregulation of Cx43 induced by stretch was blocked by the administration of actin and microtubule inhibitors, while NEDD4, a key element in mediating Cx43 protein ubiquitination and degradation, was not changed under the stretch condition. In conclusion, upregulation of Cx43 expression under the 24 h stretch condition is mediated via TGF beta1 receptor signaling pathway, and it also involves the actin and microtubule cytoskeletal network.
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