Abstract
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.
Highlights
Cells or tissues in normal pathophysiological conditions undergo stretch to maintain homeostasis
The immunofluorescence labeling of Cx43 was reduced after administration of SB431542 (5 μM) under the stretch condition (Figure 5b). These results clearly indicated that administration of TGF beta1 receptor inhibitor, SB431542, to human umbilical vein endothelial cells (HUVECs) under the stretch condition can partially block the effect of stretch-induced Cx43 protein expression
We found that stretch stimulation promoted the Cx43 expression in HUVECs
Summary
Cells or tissues in normal pathophysiological conditions undergo stretch to maintain homeostasis. In blood vessel smooth muscle cells, mechanical stretch is a physiological feature that occurs by regulating blood pressure and blood flow. The stomach is expanded and undergoes mechanical stretch for fulfilling its normal digestive function [1]. Gap junctions are intercellular channels that allow the direct cell to cell exchange of ions and small molecules with molecular weight less than 1,000 Da such as water, ATP, calcium, CAMP, CGMP, IP3, etc. Gap junctional intercellular communications play pivotal roles in maintaining the physiological function of cells and tissues, which include cell differentiation, proliferation, survival, apoptosis, and tissue homeostasis [2]. There are 21 connexin genes in the human genome and, among these connexins, connexin (Cx43) is the most widely distributed gap junction protein in different cells [3]
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