Loss of Rab22a prevents Angiotensin II-induced Hypertension and vascular dysfunction by inhibiting AT1R recyling
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ABSTRACT:
PROVIDER: PRJNA690944 | ENA |
REPOSITORIES: ENA
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Project description:The goals of this study is to compare the differently expressed genes in abdominal aorta of Rab22a KO mice and Rab22a WT mice with or without Angiotensin II treatment for 14 days at the concentration of 500ng/kg/min.The mice (n=20) were randomly divided into 4 groups:WT+AngII,WT+NS,KO+AngII,KO+NS (n = 5 for each group). Mice in WT+NS and KO+NS groups were infused with saline or 500 ng/kg/min of WT+AngII and KO+AngII respectively. Then the abdominal aorta were used to identify differentially expressed genes among different groups.
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Project description:Renin-angiotensin system (RAS) inhibition reduces stroke and improves brain capillary integrity in stroke prone spontaneously hypertensive rats (SHRSP). We tested the hypothesis that treatment with an angiotensin II receptor subtype 1 (AT1R) antagonist has different effects, compared to an angiotensin converting enzyme (ACE) inhibitor, on gene expression in blood-brain barrier (BBB) capillaries. Six weeks old SHRSP were treated with either olmesartan (4 mg/kg, n=20), lisinopril (6 mg/kg , n=20) or remained untreated (n=20). Blood pressure was controlled by tail-cuff measurement. After 5 weeks the animals were sacrificed and cerebral capillaries were isolated. mRNA was extracted and analyzed with rat GeneChip DNA arrays. Additionally, brain histology and monocyte/macrophage infiltrates were determined. Both treatments similarly reduced neurological signs of stroke, stroke mortality, and monocyte/macrophage infiltration, compared to controls. Blood pressure was not influenced significantly by both drugs. We found 42 transcripts that were regulated by both treatments in the same manner. These genes were mostly related to inflammation. We also observed 39 differentially expressed genes between the two treatment groups that typically contribute to cell growth and differentiation. This study demonstrates that, despite similar effects on cerebral pathology and outcome, ACE inhibition and AT1R blockade have distinct molecular effects on gene expression in BBB capillaries.
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Project description:Genomic analysis of control and collateral arteries was used to investigate mechanisms responsible for impaired collateral growth in the Spontaneously Hypertensive rat, an animal model of essential hypertension with increased oxidative and nitrosative stress and metabolic abnormalities. A fundamental difference was observed in the overall expression pattern in SHR vs WKY collaterals. Redox related genes with altered expression included cyba (the gene encoding p22phox), superoxide dismutase 3, and thioredoxin reductases 1 and 2. Cystatin C, hevin, angiotensinogen, and the angiotensin type 1b receptor (AT1bR) had altered collateral expression that was confirmed by RT-PCR. These molecules are known to have significant roles in other types of arterial remodeling. Of specific interest was the AT1bR which exhibited up-regulation in WKY collaterals, but down-regulation in SHR. A remarkable increase in AT1R protein was observed in WKY but not SHR collaterals. Pharmacological blockade of the AT1R with losartan prevented collateral luminal expansion in WKY. In SHR, captopril restored redox status assessed by cyba expression and nitric oxide concentration, prevented collateral AT1bR down-regulation and re-established the capacity for collateral growth. These results indicate that redox-status significantly alters flow-mediated transcriptional regulation and demonstrate that increased flow-related expression/activation of the AT1R is required for normal collateral luminal expansion but is altered by chronic oxidative and/or nitrosative stress in hypertensive rats. Keywords: gene expression two strains: two vessel types
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Project description:Hypertension induced with chronic or acute angiotensin treatment in mouse. Related experiment E-TIGR-11
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Project description:Oxidative injury and inflammation have been implicated in the genesis of hypertension but the mechanisms involved are not fully understood. We describe a new pathway in which angiotensin II promotes dendritic cell (DC) activation of T cells and ultimately hypertension. NADPH oxidase-dependent superoxide production is increased 5-fold in DCs isolated from hypertensive mice as compared to sham-treated mice. This is associated with DC accumulation of protein-isoketal adducts and production of IL-6, IL-1β and IL-23. DCs from hypertensive mice but not sham mice promote survival and proliferation of CD8+ T cells in culture. Chemically diverse isoketal scavengers not only prevent activation and immunogenicity of DCs, but also attenuate angiotensin II-induced hypertension. Moreover, adaptive transfer of DCs from hypertensive mice prime development of hypertension in response to a subpressor dose of angiotensin II. Exposure of DCs to tert butyl hypdroperoxide promoted isoketal formation, DC stimulation of CD8+ T cell proliferation and primed hypertension in response to low dose angiotensin II. Serum isoprostanes, precursors to isoketals, were found to be elevated in humans with treated hypertension and were markedly elevated in patients with resistant hypertension. These studies show that angiotensin II-induced hypertension activates DCs, in large part by causing superoxide production and formation of isoketals. They define a new mechanism of hypertension and identify a potential new therapeutic approach for this disease. We used microarrays to detail the expression differences in dendritic cells under hypertensive conditions. Dendritic cells were isolated from mosue spleen and subsequently treated with Angiotensin II with or without co-treatment with 2-hydroxybenzylamine (2-HOBA) for RNA extraction and hybridization on Affymetrix microarrays. We sought to determine the effect of oxidative stress on dendritic cell expression profiles.
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