Estrogen dependent CD4+ T cell specific transcriptomic pathways identified in premenopausal protection against hypertension
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ABSTRACT:
PROVIDER: PRJNA667068 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12765162_1.fastq.gz | Fastqsanger.gz | |||
| SRR12765162_2.fastq.gz | Fastqsanger.gz | |||
| SRR12765163_1.fastq.gz | Fastqsanger.gz | |||
| SRR12765163_2.fastq.gz | Fastqsanger.gz | |||
| SRR12765164_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Premenopausal females are protected against T cell-dependent immune activation and development of angiotensin II (Ang II) hypertension compared to males and postmenopausal females. Therefore, the current study hypothesized that specific CD4+ T cell pathways are regulated by estrogen signlaing and Ang II, and contribute to sex differences in T cell cytokine secretion and renal inflammation. Methods and Results: Transcriptomic profiles of CD4+ T cells isolated from spleens of untreated (Control) and Ang II infused (Ang II) premenopausal C57BL/6 mice were examined via RNA sequencing. Ang II significantly regulated expression of 34 genes, of which 11 (Upregulated: CD163, PRG2, S100A9, MPO, CTSG, NGP, LCN2, S100A8; Downregulated: MARCO, IL1b, HSPA1B) were confirmed by real-time PCR. To determine the effect of estrogen on premenopausal expression of RNAseq identifed genes during Ang II infusion we used two models of estrogen signlaing disruption. Both animal wide knockdown of estrogen receptor a and 4-vinylcyclohexene diepoxide (VCD) induction of menopause, significantly altered expression of RNAseq identified genes. To examine the effect of T cell activation on RNAseq gene expression, CD4+ T cells from control and Ang II treated premenopausal and male mice were stimulated in vitro. Sex differences in T cell RNAseq gene expression were associated with sex differences in supernatant concentration of IL10, IL4, and IFNg and renal IL10, IL4, and IL2 content. Conclusions: These estrogen dependent T cell transcriptomic pathways and sex dependent functional differences in T cell cytokine secretion identify novel pathways that may mediate sex specific inflammatory responses during hypertension development.
2020-10-03 | GSE158946 | GEO
Project description:Menopause is associated with an increase in the prevalence and severity of hypertension in women. Although premenopausal females are protected against T cell-dependent immune activation and development of angiotensin II (Ang II) hypertension, this protection is lost in postmenopausal females. Therefore, the current study hypothesized that specific CD4+ T cell pathways are regulated by sex hormones and Ang II to mediate progression from premenopausal protection to postmenopausal hypertension. Menopause was induced in C57BL/6 mice via repeated 4-vinylcyclohexene diepoxide (VCD) injections, while premenopausal females received sesame oil vehicle. A subset of premenopausal mice and all menopausal mice were infused with Ang II for 14 days (Control, Ang II, Meno/Ang II). Proteomic and phosphoproteomic profiles of CD4+ T cells isolated from spleens were examined.Ang II markedly increased CD4+ T cell protein abundance and phosphorylation associated with DNA and histone methylation in both premenopausal and postmenopausal females. Compared to premenopausal T cells, Ang II infusion in menopausal mice increased T cell phosphorylation of MP2K2, an upstream regulator of ERK, and was associated with upregulated phosphorylation at ERK targeted sites. Additionally, Ang II infusion in menopausal mice decreased T cell phosphorylation of TLN1, a key regulator of IL-2R and FOXP3 expression. These findings identify novel, distinct intracellular T cell pathways that influence T cell-mediated inflammation during postmenopausal hypertension.
2021-09-09 | PXD021233 | Pride
Project description:Highly efficacious antiviral protection of plants by siRNAs identified in vitro
| PRJNA497995 | ENA
Project description:Background: Clinical trial and epidemiological data support that the cardiovascular effects of estrogen are complex, including a mixture of both potentially beneficial and harmful effects. In animal models, estrogen protects females from vascular injury and inhibits atherosclerosis. These effects are mediated by estrogen receptors (ERs), which when bound to estrogen can bind to DNA to directly regulate transcription. ERs can also activate several cellular kinases by inducing a “rapid” non-nuclear signaling cascade. However, the biologic significance of this rapid signaling pathway has been unclear. Methods and Results: Here, we develop a novel transgenic mouse in which rapid signaling is blocked by over-expression of a peptide that prevents ERs from interacting with the scaffold protein, striatin (the Disrupting Peptide Mouse, DPM). Microarray analysis of ex vivo-treated mouse aortas demonstrates that rapid ER signaling plays an important role in E2-mediated gene regulatory responses. Disruption of ER-striatin interactions also eliminates the ability of E2 to stimulate cultured endothelial cell migration and to inhibit cultured vascular smooth muscle cell growth. The importance of these findings is underscored by in vivo experiments demonstrating loss of estrogen-mediated protection against vascular injury in the DPM mouse following carotid artery wire injury. Conclusions: Taken together, these results support that rapid, non-nuclear ER signaling contributes to the transcriptional regulatory functions of ER, and is essential for many of the vasoprotective effects of estrogen. These findings also identify the rapid ER signaling pathway as a potential target for the development of novel therapeutic agents.
2012-09-01 | GSE35558 | GEO
Project description:Background: Clinical trial and epidemiological data support that the cardiovascular effects of estrogen are complex, including a mixture of both potentially beneficial and harmful effects. In animal models, estrogen protects females from vascular injury and inhibits atherosclerosis. These effects are mediated by estrogen receptors (ERs), which when bound to estrogen can bind to DNA to directly regulate transcription. ERs can also activate several cellular kinases by inducing a M-bM-^@M-^\rapidM-bM-^@M-^] non-nuclear signaling cascade. However, the biologic significance of this rapid signaling pathway has been unclear. Methods and Results: Here, we develop a novel transgenic mouse in which rapid signaling is blocked by over-expression of a peptide that prevents ERs from interacting with the scaffold protein, striatin (the Disrupting Peptide Mouse, DPM). Microarray analysis of ex vivo-treated mouse aortas demonstrates that rapid ER signaling plays an important role in E2-mediated gene regulatory responses. Disruption of ER-striatin interactions also eliminates the ability of E2 to stimulate cultured endothelial cell migration and to inhibit cultured vascular smooth muscle cell growth. The importance of these findings is underscored by in vivo experiments demonstrating loss of estrogen-mediated protection against vascular injury in the DPM mouse following carotid artery wire injury. Conclusions: Taken together, these results support that rapid, non-nuclear ER signaling contributes to the transcriptional regulatory functions of ER, and is essential for many of the vasoprotective effects of estrogen. These findings also identify the rapid ER signaling pathway as a potential target for the development of novel therapeutic agents. Transgenic disrupting peptide mice (DPM) express the Estrogen Receptor (ER) alpha amino acids 176-253 peptide under CMV promoter control. This peptide blocks interactions between ER and striatin, which inhibits rapid non-genomic signaling by ER to cellular kinases. Female WT and DPM mice (4 mice per sample) were overiectomized, and 1 week later aortas were harvested and treated + 10 nM beta-estradiol (E2) or + EtOH vehicle (Veh) for 4 hrs ex vivo. Total RNA was collected, reverse transcribed to cDNA and used to probe Affymetrix mouse 430.A 2.0 arrays.
2012-09-01 | E-GEOD-35558 | biostudies-arrayexpress
Project description:Transferrable protection by gut microbes against STING-associated lung disease
| PRJEB42379 | ENA
Project description:This study investigated sex differences in the sensitization of angiotensin (ANG) II-induced hypertension and the role of central estrogen and ANG-(1-7) in this process. Male and female rats were implanted for telemetered blood pressure (BP) recording. A subcutaneous subpressor dose of ANG II was given alone or concurrently with intracerebroventricular estrogen, ANG-(1-7), an ANG-(1-7) receptor antagonist A-779 or vehicle for 1 wk (induction). After a 1-wk rest (delay), a pressor dose of ANG II was given for 2 wk (expression). In males and ovariectomized females, subpressor ANG II had no sustained effect on BP during induction, but produced an enhanced hypertensive response to the subsequent pressor dose of ANG II during expression. Central administration of estrogen or ANG-(1-7) during induction blocked ANG II-induced sensitization. In intact females, subpressor ANG II treatment produced a decrease in BP during induction and delay, and subsequent pressor ANG II treatment given during expression produced only a slight but significant increase in BP. However, central blockade of ANG-(1-7) by intracerebroventricular infusion of A-779 during induction restored the decreased BP observed in females during induction and enhanced the pressor response to the ANG II treatment during expression. RT-PCR analyses indicated that estrogen given during induction upregulated mRNA expression of the renin-angiotensin system (RAS) antihypertensive components, whereas both central estrogen and ANG-(1-7) downregulated mRNA expression of RAS hypertensive components in the lamina terminalis. The results indicate that females are protected from ANG II-induced sensitization through central estrogen and its regulation of brain RAS.
| S-EPMC4101642 | biostudies-literature
Project description:17β-estradiol (E2) exerts complex and context-dependent effects in pulmonary hypertension. In hypoxia-induced pulmonary hypertension (HPH), E2 attenuates lung vascular remodeling through estrogen receptor (ER)-dependent effects; however, ER target genes in the hypoxic lung remain unknown. In order to identify the genome regulated by the E2-ER axis in the hypoxic lung, we performed a microarray analysis in lungs from HPH rats treated with E2 (75 mcg/kg/d) ± ER-antagonist ICI182,780 (3 mg/kg/d). Untreated HPH rats and normoxic rats served as controls. Using a false discovery rate of 10%, we identified a significantly differentially regulated genome in E2-treated vs. untreated hypoxia rats. Genes most up-regulated by E2 encoded matrix metalloproteinase 8, S100 calcium binding protein A8, and IgA Fc receptor; genes most down-regulated by E2 encoded olfactory receptor 63, secreted frizzled-related protein 2, and thrombospondin 2. Several genes affected by E2 changed in the opposite direction after ICI182,780 co-treatment, indicating an ER-regulated genome in HPH lungs. The bone morphogenetic protein antagonist Grem1 (gremlin 1) was up-regulated by hypoxia, but found to be among the most down-regulated genes after E2 treatment. Gremlin 1 protein was reduced in E2-treated vs. untreated hypoxic animals, and ER-blockade abolished the inhibitory effect of E2 on Grem1 mRNA and protein. In conclusion, E2 ER-dependently regulates several genes involved in proliferative and inflammatory processes during hypoxia. Gremlin 1 is a novel target of the E2-ER axis in HPH. Understanding the mechanisms of E2 gene regulation in HPH may allow for selectively harnessing beneficial transcriptional activities of E2 for therapeutic purposes.
2017-08-01 | GSE85618 | GEO
Project description:Adipose Mesenchymal Cells-Derived Extracellular Vesicles Alleviate DOCA-salt-Induced Hypertension by Promoting Cardio-Renal Protection
| PRJNA586838 | ENA
Project description:Purpose: While women are more susceptible to pulmonary arterial hypertension (PAH) than men, their right ventricular (RV) function is better preserved. Experimental studies have identified estrogen receptor alpha (ERα) as a likely mediator for estrogen protection in the RV. However, the role of ERα in preserving RV function and remodeling during pressure overload remains poorly understood. We hypothesized that loss of functional ERα removes female protection from adverse remodeling and is permissive for development of a maladapted RV phenotype. Methods: Male and female rats with a loss-of-function mutation in ERα (ERαMut) and wildtype (WT) littermates, while at their surgical plane of anesthesia, underwent RV pressure overload by pulmonary artery banding (PAB) or a sham surgery. Results: At 10 weeks post-PAB, WT and ERαMut demonstrated RV hypertrophy. Single beat analysis and Tau Weiss calculation from RV pressure waveforms (collected during surgical plane of anesthesia) demonstrated uncoupling of the RV-pulmonary vascular circuit and diastolic dysfunction, respectively, in female, but not male, ERαMut PAB rats. Similarly, female, but not male, ERαMut exhibited increased RV fibrosis, comprised primarily of stiffer collagen type I, suggesting RV stiffening by collagen type I accumulation. RNA-sequencing in female WT and ERαMut RV revealed Kallikrein related-peptidase 10 (Klk10) and Jun Proto-Oncogene (Jun) as possible mediators of female RV protection during PAB. Conclusions: ERα in females is protective against RV-pulmonary vascular uncoupling, diastolic dysfunction, and fibrosis in response to pressure overload. ERα appears to be dispensable for RV adaptation in males. ERα may be a mediator of superior RV adaptation in female patients with PAH.
2020-04-11 | GSE148453 | GEO