Modeling horizontal and vertical variation in intraurban exposure to PM2.5 concentrations and compositions.

Land use regression (LUR) models are increasingly used to evaluate intraurban variability in population exposure to fine particulate matter (PM2.5). However, most of these models lack information on PM2.5 elemental compositions and vertically distributed samples. The purpose of this study was to evaluate intraurban exposure to PM2.5 concentrations and compositions for populations in an Asian city using LUR models, with special emphasis on examining the effects of having measurements on different building stories. PM2.5 samples were collected at 20 sampling sites below the third story (low-level sites). Additional vertically stratified sampling sites were set up on the fourth to sixth (mid-level sites, n=5) and seventh to ninth (high-level sites, n=5) stories. LUR models were built for PM2.5, copper (Cu), iron (Fe), potassium (K), manganese (Mn), nickel (Ni), sulfur (S), silicon (Si), and zinc (Zn). The explained concentration variance (R(2)) of the PM2.5 model was 65%. R(2) values were >69% in the Cu, Fe, Mn, Ni, Si, and Zn models and <44% in the K and S models. Sampling height from ground level was a significant predictor in the PM2.5 and Si models. This finding stresses the importance of collecting vertically stratified information on PM2.5 mass concentrations to reduce potential exposure misclassification in future health studies. In addition to traffic variables, some models identified gravel-plant, industrial, and port variables with large buffer zones as important predictors, indicating that PM from these sources had significant effects at distant places.

Identifying the regulatory element for human angiotensin-converting enzyme 2 (ACE2) expression in human cardiofibroblasts.

Angiotensin-converting enzyme 2 (ACE2) has been proposed as a potential target for cardioprotection in regulating cardiovascular functions, owing to its key role in the formation of the vasoprotective peptides angiotensin-(1-7) from angiotensin II (Ang II). The regulatory mechanism of ace2 expression, however, remains to be explored. In this study, we investigated the regulatory element within the upstream of ace2. The human ace2 promoter region, from position -2069 to +20, was cloned and a series of upstream deletion mutants were constructed and cloned into a luciferase reporter vector. The reporter luciferase activity was analyzed by transient transfection of the constructs into human cardiofibroblasts (HCFs) and an activating domain was identified in the -516/-481 region. Deletion or reversal of this domain within ace2 resulted in a significant decrease in promoter activity. The nuclear proteins isolated from the HCFs formed a DNA-protein complex with double stranded oligonucleotides of the -516/-481 domain, as detected by electrophoretic mobility shift assay. Site-directed mutagenesis of this region identified a putative protein binding domain and a potential binding site, ATTTGGA, homologous to that of an Ikaros binding domain. This regulatory element was responsible for Ang II stimulation via the Ang II-Ang II type-1 receptor (AT1R) signaling pathway, but was not responsible for pro-inflammatory cytokines TGF-ß1 and TNF-α. Our results suggest that the nucleotide sequences -516/-481 of human ace2 may be a binding domain for an as yet unidentified regulatory factor(s) that regulates ace2 expression and is associated with Ang II stimulation.

Regulation of angiotensin converting enzyme II by angiotensin peptides in human cardiofibroblasts.

Numerous studies have suggested that angiotensin peptides modulate the expression of angiotensin converting enzyme II (ACE2) in the cardiovascular system, but the molecular mechanisms remain poorly understood. In the present study, human cardiac fibroblasts (HCF) were used to test the regulatory effects of angiotensin II (Ang II) and angiotensin-(1-7) [Ang-(1-7)] on ACE2 expression. The results show that Ang II upregulates ACE2 expression. This action is modulated through activation of Ang II type 1 receptor (AT1R). Ang II-mediated ACE2 upregulation was blocked by antagonists of AT1R and ERK-MAPK signaling pathways. Additionally, Ang-(1-7) increased ACE2 expression, and this upregulation was inhibited by Ang-(1-7) Mas receptor blockade. Our results further reveal that the activation of p-ERK1/2 proteins plays a critical role in upregulating ACE2 in Ang-(1-7)-stimulated HCF cells. This effect occurs independently of the Ang II-AT1R signaling pathway. In conclusion, we propose that Ang II-upregulated ACE2 may increase Ang-(1-7) formation from Ang II, and that ACE2 expression is further enhanced by Ang-(1-7) in a positive feedback loop.