Angiotensin II Signal Transduction Through Small GTP-Binding Proteins

Ohtsu, Haruhiko; Suzuki, Hiroyuki; Nakashima, Hisashi; Dhobale, Sudhir; Frank, Gerald D.; Motley, Evangeline D.; Eguchi, Satoru

doi:10.1161/01.hyp.0000237975.90870.eb

Cited by 87 publications

(43 citation statements)

References 76 publications

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“…Our finding that HDL reduces AT1R expression and subsequent Ang II-mediated signaling supports the recent observation of Tölle et al, 16 who demonstrated that HDL decreases NOX-dependent ROS generation via inhibition of the activation of Rac1, which is a downstream AT1R-dependent mediator of Ang II. 26 We suggest that reduced peroxynitrite formation as a result of lower NOX activity, 27 after apo A-I transfer, decreased eNOS uncoupling and improved NO bioavailability, as evidenced by improved endothelial function. In addition, the increased eNOS dimer:monomer ratio, as a consequence of reduced NOX activity, 28 may also have contributed to enhanced NO bioavailability, because oxygen reduction is always uncoupled from NO formation in monomers.…”

Section: Discussionmentioning

confidence: 80%

“…26 We suggest that reduced peroxynitrite formation as a result of lower NOX activity, 27 after apo A-I transfer, decreased eNOS uncoupling and improved NO bioavailability, as evidenced by improved endothelial function. In addition, the increased eNOS dimer:monomer ratio, as a consequence of reduced NOX activity, 28 may also have contributed to enhanced NO bioavailability, because oxygen reduction is always uncoupled from NO formation in monomers.…”

Section: Van Linthout Et Al Hdl and At1 Receptormentioning

confidence: 82%

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Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor

et al. 2009

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Abstract-There is growing evidence that a cross-talk exists between the renin-angiotensin (Ang) system and lipoproteins.We investigated the role of high-density lipoprotein (HDL) on Ang II type 1 receptor (AT1R) regulation and subsequent Ang II-mediated signaling under diabetic conditions. To investigate the effect of HDL on AT1R expression in vivo, apolipoprotein A-I gene transfer was performed 5 days after streptozotocin injection. Six weeks after apolipoprotein A-I gene transfer, the 1.9-fold (Pϭ0.001) increase of HDL cholesterol was associated with a 4.7-fold (PϽ0.05) reduction in diabetes mellitus-induced aortic AT1R expression. Concomitantly, NAD(P)H oxidase activity, Nox 4, and p22 phox mRNA expression were reduced 2.6-fold, 2.0-fold, and 1.5-fold (PϽ0.05), respectively, whereas endothelial NO synthase dimerization was increased 3.3-fold (PϽ0.005). Apolipoprotein A-I transfer improved NO bioavailability as indicated by ameliorated acetylcholine-dependent vasodilation in the streptozotocin-Ad.hapoA-I group compared with streptozotocin-induced diabetes mellitus. In vitro, HDL reduced the hyperglycemia-induced upregulation of the AT1R in human aortic endothelial cells. This was associated with a 1.3-fold and 2.2-fold decreases in reactive oxygen species and NAD(P)H oxidase activity, respectively (PϽ0.05). Finally, HDL reduced the responsiveness to Ang II, as indicated by decreased oxidative stress in the hyperglycemiaϩHDLϩAng II group compared with the hyperglycemiaϩAng II group. In conclusion, vascular-protective effects of HDL include the downregulation of the AT1R. Diabetes mellitus is associated with endothelial dysfunction, an early phase of atherosclerosis further characterized by a reduction in NO bioavailability, without significant morphological changes of the vessel wall. 1,2 Both diabetes mellitus-associated hyperglycemia and increased angiotensin (Ang) II levels 3 induce reactive oxygen species (ROS), which contribute to endothelial dysfunction, partly via oxidative degradation of NO. Recent studies have demonstrated that ROS are predominantly produced by vascular NAD(P)H oxidase (NOX), 4 whereas "uncoupled" endothelial NO synthase (eNOS; when eNOS produces O 2 ⅐Ϫ rather then NO) is another important source of ROS in diseased, including diabetic, blood vessels. 5 Numerous studies have shown that activation of the Ang II type 1 receptor (AT1R) contributes to the induction of oxidative stress and apoptosis of vascular cells, thus contributing to the initiation and progression of endothelial dysfunction. 6 Ang II not only increases NOX activity but also uncouples eNOS in diabetic mice. 7 The expression levels of the AT1R define the biological efficacy of Ang II and have been shown to be regulated by several agonists, such as Ang II, glucose, insulin, ROS, low-density lipoprotein (LDL), and many others, 8,9 including diabetes mellitus. 10,11 The importance of the enhanced vascular AT1R expression and Ang II-mediated signaling in diabetes mellitus-associated endothelial dysfunction follows from the ...

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Section: Discussionmentioning

confidence: 80%

Section: Van Linthout Et Al Hdl and At1 Receptormentioning

confidence: 82%

Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor

et al. 2009

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“…In addition, only DN-MEK1 inhibited OPN promoter activity among kinase-inactive mutants of the MAP kinase family. Thus, while Ang II also activates small G proteins, Rac, Rho, and other MAP kinases (e.g., JNK and p38MAPK) (21), the Ras-MEK1-ERK axis appears to be the primary mediator of Ang II-induced OPN expression. Interestingly, inhibition of Ras by dominant-negative Ras or pharmacological inhibitors attenuates atherosclerosis and neointimal formation after balloon injury (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…Ang II also activates multiple small GTP-binding proteins (21). Therefore, to study the role of the small G proteins, we performed reporter gene assays using the luciferase reporter construct for OPN, OPN-1500Luc.…”

Section: Role Of G Proteins In Ang Ii-induced Opn Expressionmentioning

confidence: 99%

Angiotensin II-Induced Osteopontin Expression in Vascular Smooth Muscle Cells Involves Gq/11, Ras, ERK, Src and Ets-1

et al. 2008

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“…26 Also, Ang II induces cardiovascular tissue remodelling, proliferation, migration and hypertrophy through activation of several small G proteins including Ras, Rho and Rac. 27 RAASmediated oxidative stress results in activation of the JAK/STAT, Akt (protein Kinase B), and P38 MAPK pathways, which are implicated in the regulation of gene transcription and cell migration. In addition, RAAS activation results in increased signalling through the Rho and Rho Kinase pathways, which also participate in the development of hypertrophy, VSMCs migration, proliferation, inflammation, and hyperplasia in cardiovascular tissue.…”

Section: Non-genomic Actions Of Aldosterone and The Metabolic Syndrommentioning

confidence: 99%

Role of aldosterone and angiotensin II in insulin resistance: an update

Lastra-Lastra

Sowers

Restrepo-Erazo

et al. 2009

Clinical Endocrinology

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SummaryThe role of the Renin-Angiotensin-Aldosterone system (RAAS) on the development of insulin resistance and cardiovascular disease is an area of growing interest. Most of the deleterious actions of the RAAS on insulin sensitivity appear to be mediated through activation of the Angiotensin II (Ang II) Receptor type 1 (AT 1 R) and increased production of mineralocorticoids. The underlying mechanisms leading to impaired insulin sensitivity remain to be fully elucidated, but involve increased production of reactive oxygen species and oxidative stress. Both experimental and clinical studies also implicate aldosterone in the development of insulin resistance, hypertension, endothelial dysfunction, cardiovascular tissue fibrosis, remodelling, inflammation and oxidative stress. There is abundant evidence linking aldosterone, through non-genomic actions, to defective intracellular insulin signalling, impaired glucose homeostasis and systemic insulin resistance not only in skeletal muscle and liver but also in cardiovascular tissue. Blockade of the different components of the RAAS, in particular Ang II and AT 1 R, results in attenuation of insulin resistance, glucose homeostasis, as well as decreased cardiovascular disease morbidity and mortality. These beneficial effects go beyond to those expected with isolated control of hypertension. This review focuses on the role of Ang II and aldosterone in the pathogenesis of insulin resistance, as well as in clinical relevance of RAAS blockade in the prevention and treatment of the metabolic syndrome and cardiovascular disease.

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Angiotensin II Signal Transduction Through Small GTP-Binding Proteins

Cited by 87 publications

References 76 publications

Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor

Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor

Angiotensin II-Induced Osteopontin Expression in Vascular Smooth Muscle Cells Involves Gq/11, Ras, ERK, Src and Ets-1

Role of aldosterone and angiotensin II in insulin resistance: an update

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