Angiotensin II Increases Urokinase-Type Plasminogen Activator Expression and Induces Aneurysm in the Abdominal Aorta of Apolipoprotein E-Deficient Mice

Wang, Yixin; Martin-McNulty, Baby; Freay, Ana D.; Sukovich, Drew; Halks-Miller, Meredith; Li, Weiwei; Vergona, Ronald; Sullivan, M.; Morser, John; Dole, William P.; Deng, Gary G.

doi:10.1016/s0002-9440(10)62532-1

Cited by 111 publications

(131 citation statements)

References 29 publications

(33 reference statements)

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“…Dissected aortae (arch to iliac bifurcation) were placed in 1 mL of DMEM/0.1% BSA supplemented with 1X ITS (Invitrogen Life Technologies) [25], and incubated for 4 h at 37°C in 5% CO 2 . Duplicate 50 µL samples of conditioned medium were assayed for panels of 18 or 19 cytokines and chemokines using the Bio-Plex Suspension Array System (Bio-Rad Laboratories, Inc.).…”

Section: Ex Vivo Aorta Organ Culture and Cytokine Secretion Assaysmentioning

confidence: 99%

Angiotensin II induces IL-6 expression and the Jak-STAT3 pathway in aortic adventitia of LDL receptor-deficient mice

et al. 2007

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Angiotensin II (A-II), the major effector peptide of the renin angiotensin system potently accelerates progression of atherosclerosis. To investigate its effects on vascular inflammatory mechanisms, we elucidated vascular cytokine expression during early lesion development in A-II-infused atherosclerosis-prone LDLR −/− mice. Male LDLR −/− mice were placed on a "Western" high-fat diet for 4 weeks, followed by sham or A-II infusion for 7 weeks. Equal blood pressures and elevations in serum lipids were seen in both groups. Mice were sacrificed when significant AII-induced plaque development was first detectable, aortae were explanted and culture media assayed for secreted cytokines. Nine cytokines were significantly induced with interleukin-6 (IL-6) being the most highly secreted. Local IL-6 production was confirmed by in situ mRNA hybridization and immunostaining, where the most abundant IL-6 was found in the aortic adventitia, with lesser production by the medial and intimal layers. Immunofluorescence colocalization showed IL-6 expression by fibroblasts and activated macrophages. Activation of downstream IL-6 signaling mediated by the Jak-STAT3 pathway was demonstrated by inducible phospho-Tyr 705 -STAT3 formation in the adventitia and endothelium (of IL-6 +/+ mice only). These findings define cytokine profiles in the A-II infusion model and demonstrate that IL-6, produced by activated macrophages and fibroblasts in the adventitia, induces the Jak-STAT3 pathway during early A-II-induced atherosclerosis.

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Section: Ex Vivo Aorta Organ Culture and Cytokine Secretion Assaysmentioning

confidence: 99%

Angiotensin II induces IL-6 expression and the Jak-STAT3 pathway in aortic adventitia of LDL receptor-deficient mice

et al. 2007

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“…11 Atherosclerotic lesions in the aorta of ApoE À/À mice fed with a high cholesterol diet show fragmentation of the elastic lamellae and rupture of the media, 12 resulting in aneurysm formation. 4,13 These pathological changes were not observed in mice deficient in both ApoE and uPA (ApoE À/À /uPA À/À mice), 5 suggesting that uPA plays a critical role in matrix destruction and aneurysm formation. Plasminogen activator inhibitor-1 (PAI-1) is the primary endogenous inhibitor of uPA and tPA.…”

Section: Introductionmentioning

confidence: 99%

“…This generally occurs at sites where there is atherosclerotic plaque. [1][2][3] Previously, we have demonstrated that proteases, especially urokinase plasminogen activator (uPA) are highly expressed in a mouse model of AAA, 4 and that uPA deficiency decreased the incidence of AAA. 5 Vascular inflammation is a prominent feature of atherosclerotic AAA, [6][7][8] characterized by the infiltration of monocytes/macrophages and lymphocytes into the arterial wall.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice

Hs¹,

Jm²,

P³

et al. 2007

Gene Ther

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Vessel wall inflammation and matrix destruction are critical to abdominal aortic aneurysm (AAA) formation and rupture. We have previously shown that urokinase plasminogen activator (uPA) is highly expressed in experimental AAA and is essential for AAA formation and expansion. In this study, we examined the effects of overexpression of a natural inhibitor of uPA, plasminogen activator inhibitor-1 (PAI-1), on the development of angiotensin (Ang) II-induced AAA in ApoE-deficient (ApoE À/À ) mice. Mice were treated with recombinant adenovirus containing either the human PAI-1 gene (Ad5.CMV.PAI-1) or the luciferase gene (Ad5.CMV.Luc) delivered either locally by intra-adventitial injection or systemically by tail vein injection. Our results show that local delivery of the PAI-1 gene completely prevented AAA formation (0 vs 55.6% in Ad5.CMV.Luc controls, Po0.05). In contrast, systemic delivery of the PAI-1 gene did not affect AAA incidence (78 vs 90% in Ad5.CMV.Luc controls, P ¼ 0.125). Local delivery of the PAI-1 gene 2 weeks after Ang II infusion prevented further expansion of small aneurysms, but had no significant effect on the progression of larger aneurysms. These data suggest that local PAI-1 gene transfer could be used to stabilize small AAA and reduce the rate of expansion and risk of rupture.

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“…[1][2][3][4] AngII-induced atherosclerosis is characterized by intimal infiltration of leukocytes that become engorged with lipid. In contrast, AngII induction of AAAs is characterized by medial destruction, macrophage infiltration, thrombus formation, and vascular remodeling.…”

mentioning

confidence: 99%

Bone Marrow Transplantation Reveals That Recipient AT1a Receptors Are Required to Initiate Angiotensin II–Induced Atherosclerosis and Aneurysms

Cassis

Rateri

Lü

et al. 2007

ATVB

147

172

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Objective-Angiotensin II (AngII) infusion into hypercholesterolemic mice accelerates atherosclerosis and promotes formation of abdominal aortic aneurysms (AAAs). The purpose of this study was to define whether AngII interacts with receptors on infiltrating versus resident cells in promoting vascular pathologies. Methods and Results-Male LDL receptorϪ/Ϫ mice, that were either AT1a receptor ϩ/ϩ or Ϫ/Ϫ, were fed a fat enriched diet and infused with either saline or AngII. AngII-induced augmentation of atherosclerosis and formation of AAAs was ablated in AT1a receptorϪ/Ϫ mice. Bone marrow transplantation studies were performed to determine the role of AT1a receptors expressed on infiltrating cells. AT1a receptor ϩ/ϩ and Ϫ/Ϫ mice were irradiated and repopulated with bone marrow-derived stem cells of either genotype. These 4 groups of chimeric mice were infused with either saline or AngII. Repopulation of irradiated AT1a receptor ϩ/ϩ mice with Ϫ/Ϫ bone marrow-derived cells resulted in modest reductions in AngII-induced atherosclerosis. Unexpectedly, AT1a receptor-deficient recipient mice were dramatically protected from AngII-induced vascular pathologies, irrespective of donor genotype. Conclusion-

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Angiotensin II Increases Urokinase-Type Plasminogen Activator Expression and Induces Aneurysm in the Abdominal Aorta of Apolipoprotein E-Deficient Mice

Cited by 111 publications

References 29 publications

Angiotensin II induces IL-6 expression and the Jak-STAT3 pathway in aortic adventitia of LDL receptor-deficient mice

Angiotensin II induces IL-6 expression and the Jak-STAT3 pathway in aortic adventitia of LDL receptor-deficient mice

Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice

Bone Marrow Transplantation Reveals That Recipient AT1a Receptors Are Required to Initiate Angiotensin II–Induced Atherosclerosis and Aneurysms

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