Abstract 313: Protective Roles of Small GTP-Binding Protein GDP Dissociation Stimulator Against Angiotensin II-Induced Thoracic Aortic Aneurysm Formation and Rupture in Mice -A Possible Novel Therapeutic Target

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Masamichi Nogi ◽  
Kimio Satoh ◽  
Shun Kudo ◽  
Junichi Omura ◽  
Nobuhiro Kikuchi ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Thoracic Aorta ◽  
Therapeutic Target ◽  
Thoracic Aortic Aneurysm ◽  
Binding Protein ◽  
Gtp Binding Protein ◽  
Gtp Binding ◽  
Significant Difference ◽  
Novel Therapeutic

Background: Statins reduce the incidence and development of thoracic aortic aneurysm (TAA) and rupture. We have previously identified that small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins. Methods and Results: To examine the role of SmgGDS in TAA formation, Apoe -/- and Apoe -/- SmgGDS +/- (DKO) mice were infused with angiotensin II (AngII, 1,000 ng/min/kg) for 4 weeks. There was no significant difference in blood pressure between the 2 genotypes in response to the AngII treatment. However, during the follow-up, 36% of DKO mice died suddenly due to TAA rupture, whereas there was no TAA rupture in Apoe -/- mice ( P <0.05, n =14 each). Histological analysis of DKO mice showed dissections of major thoracic aorta in the early phase of AngII infusion (day 3~5). We performed ultrasound imaging every week to follow the serial changes in aortic diameters. Diameter of the ascending aorta was progressively and significantly increased in DKO mice compared with Apoe -/- mice (1.64±0.06 vs. 1.43±0.05 mm at 4 weeks, P <0.05, n =14 each), whereas that of the abdominal aorta was comparable between the 2 genotypes. Indeed, there was no significant difference in the incidence of AngII-induced abdominal aortic aneurysm (AAA) formation between the 2 genotypes (both 75%). Western blotting demonstrated that AngII-induced activations of JNK and ERK were significantly higher in the thoracic aorta of DKO mice compared with Apoe -/- mice ( P <0.01, n =6 each). For mechanistic analyses, we primary cultured aortic smooth muscle cells (AoSMCs) from the 2 genotypes. After AngII (100 nM) treatment for 24 hours, DKO AoSMCs showed significantly increased JNK activity, cyclophilin A secretion, and oxidative stress levels compared with Apoe -/- AoSMCs ( P <0.01, n =6 each). Interestingly, AngII-induced upregulation of Nrf2, a master regulator of cellular responses against environmental stresses, was significantly less in DKO AoSMCs compared with Apoe -/- AoSMCs ( P <0.01, n =6). Finally, expressions of matrix metalloproteinase-2 and -9 were significantly increased in DKO AoSMCs compared with Apoe -/- AoSMCs. Conclusions: These results suggest that SmgGDS is a novel therapeutic target for the prevention and treatment of TAA.

Angiotensin II type 2 receptor stimulation of neuronal K+ currents involves an inhibitory GTP binding protein

1994 ◽  
Vol 267 (5) ◽  
pp. C1389-C1397 ◽  
Author(s):  
J. Kang ◽  
P. Posner ◽  
C. Sumners
Keyword(s):  
Angiotensin Ii ◽  
Binding Protein ◽  
At2 Receptor ◽  
Ang Ii ◽  
Gtp Binding Protein ◽  
Gtp Binding ◽  
K Current ◽  
K Currents ◽  
Stimulation Of

Angiotensin II (ANG II) elicits an ANG II type 2 (AT2) receptor-mediated increase in outward K+ current (IK; delayed rectifier K+ current) in neurons cocultured from rat hypothalamus and brain stem. Here we have shown that the AT2-receptor-mediated stimulation of neuronal IK by ANG II (100 nM) was abolished by pretreatment of cultures with pertussis toxin (PTX; 200 ng/ml) and by intracellular application of an antibody against the inhibitory guanine nucleotide (GTP) binding protein (anti-Gi alpha, 1:200). Antibodies against other GTP binding proteins (anti-Go alpha, 1:50 and 1:200; anti-Gq/11 alpha, 1:200) did not alter the AT2-receptor-mediated stimulation of neuronal IK by ANG II (100 nM). Furthermore, this effect of ANG II (100 nM) was inhibited by the serine/threonine phosphatase inhibitor okadaic acid (1-10 nM) and by anti-type 2A protein phosphatase (PP2A) antibodies but not by the tyrosine phosphatase inhibitor sodium orthovanadate (1 mM). Thus we have identified key components (Gi and PP2A) of the signal transduction pathway that is responsible for the AT2-receptor-mediated stimulation of neuronal K+ currents.

scholarly journals Caveolin 1 is critical for abdominal aortic aneurysm formation induced by angiotensin II and inhibition of lysyl oxidase

2014 ◽  
Vol 126 (11) ◽  
pp. 785-800 ◽  
Author(s):  
Takehiko Takayanagi ◽  
Kevin J. Crawford ◽  
Tomonori Kobayashi ◽  
Takashi Obama ◽  
Toshiyuki Tsuji ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Therapeutic Target ◽  
Lysyl Oxidase ◽  
Caveolin 1 ◽  
Abdominal Aortic ◽  
Aneurysm Development ◽  
Novel Therapeutic

Caveolin 1 deficiency protected mice from abdominal aortic aneurysm development induced by angiotensin II, which is probably due to suppression of ADAM17 activation and subsequent oxidative stress. Caveolin 1 may provide a novel therapeutic target for prevention of abdominal aortic aneurysm.

Small GTP-binding Protein RalA Associates with Weibel-Palade Bodies in Endothelial Cells

1999 ◽  
Vol 82 (09) ◽  
pp. 1177-1181 ◽  
Author(s):  
Hubert de Leeuw ◽  
Pauline Wijers-Koster ◽  
Jan van Mourik ◽  
Jan Voorberg
Keyword(s):  
Endothelial Cells ◽  
Binding Proteins ◽  
Binding Protein ◽  
Control Release ◽  
Small Gtpase ◽  
Gtp Binding Protein ◽  
Two Dimensional Gel Electrophoresis ◽  
Gtp Binding Proteins ◽  
Dense Granules ◽  
Gtp Binding

SummaryIn endothelial cells von Willebrand factor (vWF) and P-selectin are stored in dense granules, so-called Weibel-Palade bodies. Upon stimulation of endothelial cells with a variety of agents including thrombin, these organelles fuse with the plasma membrane and release their content. Small GTP-binding proteins have been shown to control release from intracellular storage pools in a number of cells. In this study we have investigated whether small GTP-binding proteins are associated with Weibel-Palade bodies. We isolated Weibel-Palade bodies by centrifugation on two consecutive density gradients of Percoll. The dense fraction in which these subcellular organelles were highly enriched, was analysed by SDS-PAGE followed by GTP overlay. A distinct band with an apparent molecular weight of 28,000 was observed. Two-dimensional gel electrophoresis followed by GTP overlay revealed the presence of a single small GTP-binding protein with an isoelectric point of 7.1. A monoclonal antibody directed against RalA showed reactivity with the small GTP-binding protein present in subcellular fractions that contain Weibel-Palade bodies. The small GTPase RalA was previously identified on dense granules of platelets and on synaptic vesicles in nerve terminals. Our observations suggest that RalA serves a role in regulated exocytosis of Weibel-Palade bodies in endothelial cells.

Rap1b Association with the Platelet Cytoskeleton Occurs in the Absence of Glycoproteins IIb/IIIa

1998 ◽  
Vol 79 (04) ◽  
pp. 832-836 ◽  
Author(s):  
Thomas Fischer ◽  
Christina Duffy ◽  
Gilbert White
Keyword(s):  
Molecular Weight ◽  
Divalent Cation ◽  
Binding Proteins ◽  
Binding Protein ◽  
Platelet Membrane ◽  
Low Molecular Weight ◽  
Membrane Glycoproteins ◽  
Gtp Binding Protein ◽  
Gtp Binding Proteins ◽  
Gtp Binding

SummaryPlatelet membrane glycoproteins (GP) IIb/IIIa and rap1b, a 21 kDa GTP binding protein, associate with the triton-insoluble, activation-dependent platelet cytoskeleton with similar rates and divalent cation requirement. To examine the possibility that GPIIb/IIIa was required for rap1b association with the cytoskeleton, experiments were performed to determine if the two proteins were linked under various conditions. Chromatography of lysates from resting platelets on Sephacryl S-300 showed that GPIIb/IIIa and rap1b were well separated and distinct proteins. Immunoprecipitation of GPIIb/IIIa from lysates of resting platelets did not produce rap1b or other low molecular weight GTP binding proteins and immunoprecipitation of rap1b from lysates of resting platelets did not produce GPIIb/IIIa. Finally, rap1b was associated with the activation-dependent cytoskeleton of platelets from a patient with Glanzmann’s thrombasthenia who lacks surface expressed glycoproteins IIb and IIIa. Based on these findings, we conclude that no association between GPIIb/IIIa and rap1b is found in resting platelets and that rap1b association with the activation-dependent cytoskeleton is at least partly independent of GPIIb/IIIa.

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