MAPK/AP-1 pathway activation mediates AT1R upregulation and vascular endothelial cells dysfunction under PM2.5 exposure.

Acute and chronic exposure to particulate matter (PM) 2.5 is associated with adverse health effect upon the cardiovascular (CV) system. However, the molecular mechanism by which PM2.5 evokes CV injuries has not been fully clarified. In our recent report, we demonstrate that exposure to PM2.5 leads to elevation of circulating angiotensin II (ANGII) levels and local expressions of angiotensinogen (AGT, the precursor of ANGII), angiotensin-converting enzyme (ACE) and ANGII type 1 receptor (AT1R) in the vascular endothelial cells, which subsequently instigates the oxidative stress and proinflammatory response in the vascular endothelium. In the present study, we disclosed that PM2.5 exposure induced the activation of the transcriptional factor AP-1 and its components, c-Jun and ATF2, in the human vascular endothelial cells. Although the DNA-binding sites for AP-1 were identified within the promoter regions of AGT, ACE and AT1R genes, RT-PCR and immunoblot assays indicated that AP-1 transactivation was only involved in AT1R upregulation, but did not affect the induction of AGT and ACE expression under the same conditions. Furthermore, ERKs and p38K functioned as the upstream protein kinases involving in AP-1 transactivation and AT1R upregulation under PM2.5 stimulation. In addition, the oxidative stress and proinflammatory responses in the PM2.5-treated vascular endothelial cells were significantly reduced when MAPKs and AP-1 activation were inhibited. Therefore, we conclude that PM2.5 exposure induces MAPK/AP-1 cascade activation, which contributes to AT1R upregulation and vascular endothelial dysfunction. Identifying novel therapeutic targets to alleviate AP-1 transactivation and restore AT1R expression may be helpful for the management of PM2.5-induced CV burden.

LKB1/p53/TIGAR/autophagy-dependent VEGF expression contributes to PM2.5-induced pulmonary inflammatory responses.

One of the health hazards of PM2.5 exposure is to induce pulmonary inflammatory responses. In our previous study, we demonstrated that exposing both the immortalized and primary human bronchial epithelial cells to PM2.5 results in a significant upregulation of VEGF production, a typical signaling event to trigger chronic airway inflammation. Further investigations showed that PM2.5 exposure strongly induces ATR/CHK1/p53 cascade activation, leading to the induction of DRAM1-dependent autophagy to mediate VEGF expression by activating Src/STAT3 pathway. In the current study, we further revealed that TIGAR was another transcriptional target of p53 to trigger autophagy and VEGF upregulation in Beas-2B cells after PM2.5 exposure. Furthermore, LKB1, but not ATR and CHK1, played a critical role in mediating p53/TIGAR/autophagy/VEGF pathway activation also by linking to Src/STAT3 signaling cascade. Therefore, on combination of the previous report, we have identified both ATR/CHK1/p53/DRAM1- and LKB1/p53/TIGAR- dependent autophagy in mediating VEGF production in the bronchial epithelial cells under PM2.5 exposure. Moreover, the in vivo study further confirmed VEGF induction in the airway potentially contributed to the inflammatory responses in the pulmonary vascular endothelium of PM2.5-treated rats. Therefore, blocking VEGF expression or autophagy induction might be the valuable strategies to alleviating PM2.5-induced respiratory injuries.

IRE1α/XBP1s branch of UPR links HIF1α activation to mediate ANGII-dependent endothelial dysfunction under particulate matter (PM) 2.5 exposure.

Short- and long-term exposure to particulate matter (PM) 2.5 instigates adverse health effect upon the cardiovascular (CV) system. Disclosing the molecular events by which PM2.5 evokes CV injuries is essential in developing effective risk-reduction strategy. Here we found that rats after intratracheally instillation with PM2.5 displayed increased circulating level of ANGII, the major bioactive peptide in renin-angiotensin-system (RAS), which resulted from the elevation of ANGII production in the vascular endothelium. Further investigations demonstrated that activation of IRE1α/XBP1s branch of unfolded protein response (UPR) was essential for augmented vascular ANGII signaling in response to PM2.5 exposure, whose effects strictly depends on the assembly of XBP1s/HIF1α transcriptional complex. Moreover, ablation of IRE1/XBP1/HIFα-dependent ACE/ANGII/AT1R axis activation inhibited oxidative stress and proinflammatory response in the vascular endothelial cells induced by PM2.5. Therefore, we conclude that PM2.5 exposure instigates endoplasmic reticulum instability, leading to the induction of IRE1α/XBP1s branch of UPR and links HIF1α transactivation to mediate ANGII-dependent endothelial dysfunction. Identifying novel therapeutic targets to alleviate ER stress and restore local RAS homeostasis in the endothelium may be helpful for the management of PM2.5-induced CV burden.