Hypertension is a dominating risk factor for cardiovascular disease. To characterize the genomic response to hypertension, we administered vehicle or angiotensin II to mice and performed gene expression analyses. AngII treatment resulted in a robust increase in blood pressure and altered expression of 235 genes in the aorta, including Gucy1a3 and Gucy1b3 which encode subunits of soluble guanylyl cyclase (sGC). Western blotting and immunohistochemistry confirmed repression of sGC associated with curtailed relaxation via sGC activation. Analysis of transcription factor binding motifs in promoters of differentially expressed genes identified enrichment of motifs for RBPJ, a component of the Notch signaling pathway, and the Notch coactivators FRYL and MAML2 were reduced. Gain and loss of function experiments demonstrated that JAG/NOTCH signaling controls sGC expression together with MAML2 and FRYL. Reduced expression of sGC, correlating with differential expression of MAML2 in stroke prone and spontaneously hypertensive rats was also seen and RNA-Seq data demonstrated correlations between JAG1, NOTCH3, MAML2 and FRYL and the sGC subunits GUCY1A3 and GUCY1B3 in human coronary artery. Notch signaling thus provides a constitutive drive on expression of the major nitric oxide receptor (GUCY1A3/GUCY1B3) in arteries from mice, rats, and humans, and this control mechanism is disturbed in hypertension.
Hypertension reduces soluble guanylyl cyclase expression in the mouse aorta via the Notch signaling pathway.
Specimen part
View SamplesInflammation and immune activation of the cervicovaginal mucosa are considered factors that increase susceptibility to HIV infection. It is essential to screen candidate anti-HIV microbicides for potential mucosal immunomodulatory/inflammatory effects prior to further clinical development. The goal of this study was to develop an in vitro method for preclinical evaluation of the inflammatory potential of new candidate microbicides. We compared transcriptomes of human vaginal cells (Vk2/E6E7) treated with well-characterized pro-inflammatory (PIC) and non-inflammatory (NIC) compounds. Microarraray comparative analysis allowed us to generate a panel of 20 genes that were consistently deregulated by all PICs compared to NICs, thus distinguishing between these two groups.
Gene Expression Profiling of Human Vaginal Cells In Vitro Discriminates Compounds with Pro-Inflammatory and Mucosa-Altering Properties: Novel Biomarkers for Preclinical Testing of HIV Microbicide Candidates.
Specimen part, Cell line
View SamplesTo gain insight into the changes in gene expression pattern upon Ebola infection, CD45+/+ (100% protein level) and CD45+/- (62% protein level) mice were challenged with mouse adapted Ebola virus. At time-points day 0, 1, 3, 5, 7, 9, 11 and 13, spleen tissue was harvested and splenocytes isolated. Total RNA was isolated for mRNA expression analysis. The mouse genome 430 2.0 array (Affymetrix, Inc.), which consists of over 39,000 genes in a single array, was used. Based on gene expression patterns, the variable genes were grouped into sixteen clusters. Each cluster contained genes associated with cellular immune processes, signaling, cell-cycle, complement coagulation cascade, biosynthesis/metabolism, ubiquitous genes involved in several cascades, and genes of unknown function. Interestingly, gene expression in clusters 2 and 3 were significantly downregulated by day 1 following EBOV challenge in CD45100% mice. In contrast, at day 1 following EBOV infection, the CD45 62% mice maintained gene expression patterns similar to day 0. The differences in gene expression patterns between the CD45 100% and CD45 62% splenocytes were less apparent at day 3 following infection and by days 5 and 7 they became very similar. At day 9, when wild-type mice had succumbed to the disease, the pattern in CD45 62% mice remained similar to the day 7 patterns of CD45 100% and CD45 62% mice. The pattern at days 11 and 13 in the CD45 62% mice had returned to that of day 0 CD45 100% or CD45 62% mice. These results suggested that in CD45 100% mice, subversion of the cell transcriptional machinery during the early stages of EBOV infection (day 1) might represent a major factor leading to death of the mice. In CD45 62% mice, early control of gene regulation likely provided the appropriate antiviral responses leading to regulated inflammation, immune co-stimulation, and survival.
Reduced levels of protein tyrosine phosphatase CD45 protect mice from the lethal effects of Ebola virus infection.
Specimen part
View SamplesIn order to identify potential genes that may play an important role in progression of colorectal carcinoma, we screened and validated the global gene expression using cDNA expression array on 36 CRC tissues and compared with 24 non-cancerous colorectal tissue.
Genome-wide expression analysis of Middle Eastern colorectal cancer reveals FOXM1 as a novel target for cancer therapy.
Sex
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