The Role of Nrf2 in the PM-Induced Vascular Injury Under Real Ambient Particulate Matter Exposure in C57/B6 Mice

Abstract

Short-and long-term exposure to particulate matter (PM) has been associated with cardiovascular disease (CVD). It is well recognized that oxidative stress is a potential major mechanism in PM-induced vascular injuries, in which the nuclear factor E2-related factor 2 (Nrf2) signaling pathway plays a critical role. In the current study, a Nrf2 knockout mouse model was used in combination with an individual ventilated cage (IVC)-based real-ambient PM exposure system to assess the potential vascular injury and the potential role of Nrf2 in the angiotensin II (Ang II)-associated vascular injury. After 6-or 11-week exposure to PM, the histopathology assay revealed that PM exposure resulted in the thickening of the walls of vascular. After 6 weeks exposure to PM, the ELISA assay revealed that PM exposure resulted in the elevated plasma concentration of Ang II. The expression levels of genes of interest were then further investigated with quantitative real-time PCR. Notably, the results showed that Angiotensinogen (AGT), Angiotensin converting enzyme (ACE) and Angiotensin type I receptor (AT1R) were involved in PM-induced pathological changes. Western blotting for ACE showed similar results. Moreover, the extent of vascular thickening and the Ang II elevation was most prominent in the Nrf2 gene knockout PM exposure group (KOE). Furthermore, the expression of Nrf2 downstream relevant genes (HO1, Nqo1, Gclc, Gsta4) were significantly enhanced in the wildtype PM exposure group (WTE), while those were remarkably suppressed in the Nrf2 gene knockout groups. The ELISA result of monocyte chemoattractant protein-1 (MCP-1) serum levels in the KOE group was significantly higher in relation to that in the Nrf2 knockout control group (KOC). In summary, PM exposure is associated with thickening of vascular wall, while Nrf2 knockout may further enhance this effect. A potential mechanistic contributor of such effects is the activation of ACE/ANGII/AT1R axis, in which Nrf2 played a regulatory role.

Palliative effects of carnosol on lung‐deposited pollutant particles‐induced thrombogenicity and vascular injury in mice

“… 47 Using the angiotensin II‐induced vascular injury model in mice, it has been demonstrated that exposure to particulate matter is associated with vascular wall thickening and that Nrf2 knockout mice exhibited an aggravation of this action, illustrating the important protective role played by Nrf2. 48 Our data show that carnosol restored the levels of both Nrf2 and HO‐1 which were substantially decreased by DEP exposure in the aortic tissue. These results are in complete agreement with the action of carnosol in the re‐establishment of the activity of SOD and concentration of GSH which were depleted by DEP administration.…”

Curzerene suppresses progression of human glioblastoma through inhibition of glutathione S‐transferase A4

“…8 In this study, we found that curzerene can significantly inhibit the expression of GSTA4 in the glioma cell types U251 and U87. GSTA4 is an important biphasic detoxification enzyme in human body, which is involved in the combination of GSH with reactive oxygen species, [22][23][24][25][26][27][28][29] Recently, GSTA4 has also been shown to affect the progression of colon cancer, as well, and this effect involves the proapoptotic metabolite 4-HNE. Specifically, in colon cancer, activator protein 1 regulates the production of 4-HNE by affecting the c-Jun/Nrf2 complex, which then results in an increase in the level of GSTA4 in cells.…”

“…In this study, we found that curzerene can significantly inhibit the expression of GSTA4 in the glioma cell types U251 and U87. GSTA4 is an important biphasic detoxification enzyme in human body, which is involved in the combination of GSH with reactive oxygen species, cell metabolites, chemotherapy drugs, and other potentially damaging molecules 22–29 …”

“…GSTA4 is an important biphasic detoxification enzyme in human body, which is involved in the combination of GSH with reactive oxygen species, cell metabolites, chemotherapy drugs, and other potentially damaging molecules. 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 …”

Reactive Oxygen Species Generated by Polycyclic Aromatic Hydrocarbons From Ambient Particulate Matter Enhance Vascular Smooth Muscle Cell Migration Through MMP Upregulation and Actin Reorganization

“…PAHs regulate the expression of ROS-related genes and the dependent signaling pathways Since there is evidence that CYP1A1 and transcription factor Nrf2 are protective against PAHs and ambient PM-induced pro-oxidative damage in various cell types [31,32], we investigated their alterations in PAH-treated VSMCs. The mRNA levels of CYP1A1 were dramatically increased in BaA-and BAQ-treated VSMCs in a time-dependent manner, and these alterations were only partially, but signi cantly, inhibited by NAC treatment (Fig.…”