Angiotensin II is associated with activation of NF-κB-mediated genes and downregulation of PPARs

2002 ◽  
Vol 11 (1) ◽  
pp. 21-30 ◽  
Author(s):  
Doris M. Tham ◽  
Baby Martin-McNulty ◽  
Yi-xin Wang ◽  
Dennis W. Wilson ◽  
Ronald Vergona ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Adhesion Molecule ◽  
Vascular Inflammation ◽  
Aortic Aneurysms ◽  
Intercellular Adhesion Molecule ◽  
Ang Ii ◽  
Inflammatory Genes ◽  
Apoe Ko Mice ◽  
Apoe Ko

Angiotensin II (ANG II) promotes vascular inflammation through nuclear factor-κB (NF-κB)-mediated induction of pro-inflammatory genes. The role of peroxisome proliferator-activated receptors (PPARs) in modulating vascular inflammation and atherosclerosis in vivo is unclear. The aim of the present study was to examine the effects of ANG II on PPARs and NF-κB-dependent pro-inflammatory genes in the vascular wall in an in vivo model of atherosclerosis and aneurysm formation. Six-month-old male apolipoprotein E-deficient (apoE-KO) mice were treated with ANG II (1.44 mg/kg per day for 30 days). ANG II enhanced vascular inflammation, accelerated atherosclerosis, and induced formation of abdominal aortic aneurysms. These effects of ANG II in the aorta were associated with downregulation of both PPAR-α and PPAR-γ mRNA and protein and an increase in transcription of monocyte chemotactic protein-1 (MCP-1), macrophage-colony stimulating factor (M-CSF), endothelial-selectin (E-selectin), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) throughout the entire aorta. ANG II also activated NF-κB with increases in both p52 and p65 NF-κB subunits. In summary, these in vivo results indicate that ANG II, through activation of NF-κB-mediated pro-inflammatory genes, promotes vascular inflammation, leading to acceleration of atherosclerosis and induction of aneurysm in apoE-KO mice. Downregulation of PPAR-α and -γ by ANG II may diminish the anti-inflammatory potential of PPARs, thus contributing to enhanced vascular inflammation.

Abstract 598: Deletion of Microsomal PGE Synthase-1 Decreases Oxidative Stress and Protects Against Abdominal Aortic Aneurysm Formation in Angiotensin II-Infused Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Miao Wang ◽  
Jane Stubbe ◽  
Eric Lee ◽  
Wenliang Song ◽  
Emanuela Ricciotti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Density Lipoprotein Receptor ◽  
The Impact

Microsomal (m) prostaglandin (PG) E 2 synthase(S)-1, an enzyme that catalyzes the isomerization of the cyclooxygenase (COX) product, PGH 2 , into PGE 2 , is a major source of PGE 2 in vivo . mPGES-1 deletion in mice was found to modulate experimentally evoked pain and inflammation and atherogenesis is retarded in mPGES-1 knockout (KO) mice. The impact of mPGES-1 deletion on formation of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) was studied in mice lacking the low density lipoprotein receptor (LDLR −/− ). AngII infusion increased aortic macrophage recruitment and nitrotyrosine staining while upregulating both mPGES-1 and COX-2 and urinary excretion of the major metabolite of PGE 2 (PGE-M). Deletion of mPGES-1 decreased both the incidence and severity of AAA and depressed excretion of both PGE-M and 8, 12-iso-iPF 2a -VI, which reflects lipid peroxidation in vivo . While Ang II infusion augmented prostaglandin biosynthesis, deletion of mPGES-1 resulted in rediversion to PGD 2 , reflected by its major urinary metabolite. However, deletion of the PGD 2 receptor, DP1, did not affect AAA in Ang II infused LDLR −/− mice. These observations indicate that deletion of mPGES-1 protects against AAA formation by AngII in hyperlipidemic mice, perhaps by decreasing oxidative stress. Inhibition of mPGES-1 may represent an effective treatment to limit aneurysm occurrence and expansion.

scholarly journals 5TNF-α and IL-1β Neutralization Ameliorates Angiotensin II-Induced Cardiac Damage in Male Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (7) ◽  
pp. 2677-2687 ◽  
Author(s):  
Yueli Wang ◽  
Yulin Li ◽  
Yina Wu ◽  
Lixin Jia ◽  
Jijing Wang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Adhesion Molecule ◽  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Cardiac Injury ◽  
Intercellular Adhesion Molecule ◽  
Ang Ii ◽  
Cardiac Damage ◽  
Inflammatory Infiltration ◽  
Tnf Α

Inflammation is a key event in hypertensive organ damage, and TNF-α and IL-1β are elevated in hypertension. In this study, we evaluated the effects of TNF-α and IL-1β elevation on hypertensive cardiac damage by treatment with a bifunctional inflammatory inhibitor, TNF receptor 2-fragment crystalization-IL-1 receptor antagonist (TFI), which can neutralize these 2 cytokines simultaneously. A mouse hypertension model of angiotensin II (Ang II) infusion (1500 ng/kg·min for 7 d) was induced in wild-type mice. TNF-α and IL-1β were inhibited by TFI administration (5 mg/kg, every other day), the effects of inhibition on cardiac damage were examined, and its mechanism on inflammatory infiltration was further studied in vivo and in vitro. Ang II infusion induced cardiac injury, including increased macrophage infiltration, expression of inflammatory cytokines (IL-12, IL-6, etc), and cardiac fibrosis, such as elevated α-smooth muscle actin, collagen I, and TGF-β expression. Importantly, the Ang II-induced cardiac injury was suppressed by TFI treatment. Moreover, TFI reduced the expression of adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) and monocyte chemotactic protein-1 expression in Ang II-treated hearts. Additionally, blockade of TNF-α and IL-1β by TFI reduced monocyte adherence to endothelia cell and macrophage migration. This study demonstrates that blocking TNF-α and IL-1β by TFI prevents cardiac damage in response to Ang II, and targeting these 2 cytokines simultaneously might be a novel tool to treat hypertensive heart injury.

Abstract 18182: Phosphodiesterase 10A Regulates Vascular Inflammation and Pathogenesis of Abdominal Aortic Aneurysms

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yujun Cai ◽  
Yujun Cai ◽  
Chen Yan ◽  
Raul J Guzman
Keyword(s):  
Vascular Inflammation ◽  
Critical Role ◽  
Abdominal Aortic Aneurysms ◽  
Peritoneal Macrophages ◽  
Aortic Aneurysms ◽  
Causative Role ◽  
Ang Ii ◽  
Monocyte Chemoattractant Protein 1 ◽  
Abdominal Aortic

Rationale: Abdominal aortic aneurysms (AAA) are characterized by aortic enlargement and underlying weakness of the vessel wall. Experimental and clinical evidence suggests that vascular inflammation is a central trigger of AAA formation. Phosphodiesterases (PDEs), known regulators of cyclic nucleotide signaling, play a critical role in vascular inflammation. Objective: In this study, we sought to determine the role and function of PDE10A in vascular inflammation and AAA formation. Methods and Results: Extensive evidence suggests that angiotensin II (Ang II) signaling plays an important causative role in AAA formation. Therefore, Real-time PCR array for all 22 known PDE genes was performed in control and Ang II-treated VSMCs. We observed that PDE10A elicited the highest levels of induction by Ang II among all PDEs. Moreover, we found that PDE10A was dramatically upreguated in the Ang II-infused AAA mouse model and in human AAA specimens. PDE10A was primarily expressed in medial VSMCs and infiltrating macrophages in AAA. More importantly, deficiency of PDE10A or PDE10A inhibition significantly attenuated AAA formation in vivo. In cultured VSMCs, knockdown of PDE10A with specific siRNA and inhibition of PDE10A by papaverine markedly suppressed Ang II-induced vascular cell adhesion molecule 1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and MMP2 expression. Deficiency of PDE10A also blocked lipopolysaccharide (LPS)-induced TNF-α, MCP-1, and MMP9 expression in peritoneal macrophages isolated from PDE10A knockout mice. Further mechanistic studies revealed that histone deacetylase 5 (HDAC5) plays an important role in PDE10A-regulated vascular inflammation via cAMP-dependent protein kinase (PKA). Conclusions: These findings demonstrate that PDE10A is an important regulator of vascular inflammation and AAA development. They further provide evidence for PDE10A as a potential therapeutic target for aortic aneurysms and other vascular diseases.

Abstract 1311: Bone Marrow Angiotensin II Type 1 Receptor Augments Atherosclerosis by Promoting Monocyte/Macrophage Lineage Differentiation from Hematopoietic Stem Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Yoshinori Tsubakimoto ◽  
Hiroyuki Yamada ◽  
Hirokazu Yokoi ◽  
Hiroki Takata ◽  
Hiroyuki Kawahito ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Angiotensin Ii ◽  
Hematopoietic Stem Cells ◽  
Atherosclerotic Lesion ◽  
Ang Ii ◽  
Hematopoietic Stem ◽  
Apoe Ko Mice ◽  
Apoe Ko

[BACKGROUND] The angiotensin II (Ang II) type 1 (AT 1 ) receptor is crucially involved in atherogenesis, but bone marrow (BM) AT 1 -mediated proatherogenic action remains undefined- . [METHOD AND RESULT] BM-derived mononuclear cells (BM-MNCs) more abundantly express AT 1 than VSMCs (2.2 fold) with similar affinities to Ang II. BM cells in 8-week-old apoE-deficient −/− ) or wild-type (Agtr1 + / + ) cells. Four (apoE-KO) mice were replaced with AT 1 -deficient (Agtr1 weeks after the initiation of western diet and Ang II infusion (500ng/kg/min), atherosclerotic lesion area in aortic root was examined. ApoE-KO mice reconstituted with Agtr1 −/− marrow (apoE-KO/BM-Agtr1 −/− ) showed a significant reduction in atherosclerotic lesions compared with apoE-KO/BM-Agtr1 + / + mice (55%, P <0.05). The accumulation of macrophages was attenuated in apoE-KO/BM-Agtr1 −/− mice (55%, P <0.05), concomitant with a decrease in the number of circulating Ly-6C hi monocytes (76%, P <0.01). The numbers of circulating CCR2 + and CX3CR1 + monocytes were also reduced in apoE-KO/BM-Agtr1 −/− mice (87±16 vs 298±66; CCR2 + monocyte, 72±12 vs 550±119 cells/μl; CX3CR1 + monocyte, respectively, P <0.01). Furthermore, the number of macrophage progenitor cells defined by M-CSF stimulated macrophage colony-forming unit was markedly reduced by 82 % (p<0.01) in Agtr1 −/− compared with Agtr1 + / + mice. We next examined the effect of BM-AT 1 on the number of hematopoietic stem cells (HSCs), common myeloid progenitors (CMP), and granulocyte/macrophage progenitors (GMP) to determine at which point of the lineage pathway, BM-AT 1 is involved. The number of HSCs did not differ between the two groups (3.6±0.8 vs 2.9±0.6 × 10 3 cells/tibia, P =n.s.), whereas the numbers of CMP and GMP were much lower in apoE-KO/BM-Agtr1 −/− mice (4.7±0.7 vs 10.2±1.4 ×10 3 cells/tibia, 9.9±2.7 vs 20.2±2.8 × 10 3 cells/tibia, respectively, P <0.05). [CONCLUSION] BM-MNCs expressed the abundant densities of AT1, and AT1-mediated signals on BM-MNCs exaggerated atherosclerotic lesion development. BM-AT 1 is closely implicated in the differentiation of HSCs into macrophage progenitors and the behavior of monocytes/macrophages, indicating that BM-AT 1 could be a promising therapeutic target for the prevention of cardiovascular events.

scholarly journals ICAM-1–activated Src and eNOS signaling increase endothelial cell surface PECAM-1 adhesivity and neutrophil transmigration

Blood ◽  
2012 ◽  
Vol 120 (9) ◽  
pp. 1942-1952 ◽  
Author(s):  
Guoquan Liu ◽  
Aaron T. Place ◽  
Zhenlong Chen ◽  
Viktor M. Brovkovych ◽  
Stephen M. Vogel ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Adhesion Molecule ◽  
Vascular Inflammation ◽  
Transendothelial Migration ◽  
Binding Activity ◽  
Polymorphonuclear Neutrophil ◽  
Intercellular Adhesion Molecule ◽  
No Production ◽  
Intercellular Adhesion Molecule 1

Abstract Polymorphonuclear neutrophil (PMN) extravasation requires selectin-mediated tethering, intercellular adhesion molecule-1 (ICAM-1)–dependent firm adhesion, and platelet/endothelial cell adhesion molecule 1 (PECAM-1)–mediated transendothelial migration. An important unanswered question is whether ICAM-1–activated signaling contributes to PMN transmigration mediated by PECAM-1. We tested this concept and the roles of endothelial nitric oxide synthase (eNOS) and Src activated by PMN ligation of ICAM-1 in mediating PECAM-1–dependent PMN transmigration. We observed that lung PMN infiltration in vivo induced in carrageenan-injected WT mice was significantly reduced in ICAM-1−/− and eNOS−/− mice. Crosslinking WT mouse ICAM-1 expressed in human endothelial cells (ECs), but not the phospho-defective Tyr518Phe ICAM-1 mutant, induced SHP-2–dependent Src Tyr530 dephosphorylation that resulted in Src activation. ICAM-1 activation also stimulated phosphorylation of Akt (p-Ser473) and eNOS (p-Ser1177), thereby increasing NO production. PMN migration across EC monolayers was abolished in cells expressing the Tyr518Phe ICAM-1 mutant or by pretreatment with either the Src inhibitor PP2 or eNOS inhibitor L-NAME. Importantly, phospho–ICAM-1 induction of Src signaling induced PECAM-1 Tyr686 phosphorylation and increased EC surface anti–PECAM-1 mAb-binding activity. These results collectively show that ICAM-1–activated Src and eNOS signaling sequentially induce PECAM-1–mediated PMN transendothelial migration. Both Src and eNOS inhibition may be important therapeutic targets to prevent or limit vascular inflammation.

Abstract 164: Endothelial Gab1 Limits Vascular Remodeling and Atherosclerosis Through Inhibition of Endothelial Inflammation

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Suowen Xu ◽  
Meimei Yin ◽  
Jingjing Zhao ◽  
Marina Koroleva ◽  
Zheng Gen Jin
Keyword(s):  
Adhesion Molecule ◽  
Vascular Remodeling ◽  
Fluid Shear Stress ◽  
Atherosclerotic Lesion ◽  
Monocyte Adhesion ◽  
Disturbed Flow ◽  
Apoe Ko Mice ◽  
Apoe Ko

Objective: We have previously shown that docking protein Grb2-associated binder 1 (Gab1) is a mechano-effector protein in response to fluid shear stress and regulates postnatal angiogenesis. The aim of this study was to determine the in vivo role of endothelial Gab1 in flow-mediated vascular remodeling and atherosclerosis and explore the underlying mechanisms. Methods and Results: To determine the role of endothelial Gab1 in disturbed flow-induced vascular remodeling in vivo, we performed partial carotid artery ligation in Gab1 endothelium-restricted knockout (Gab1-ecKO) mice and wild-type (WT) littermates, and we observed that Gab1-ecKO mice resulted in increased intima-media thickness. To examine the role of endothelial Gab1 in atherosclerosis, we next crossed Gab1-ecKO mice with ApoE KO mice. After partial ligation, Gab1-ecKO;ApoE KO mice under high fat diet showed increased atherosclerotic lesion size compared to Gab1-WT;ApoE KO mice. The levels of proatherogenic genes intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and leukocyte infiltration were all increased in Gab1-ecKO;ApoE KO mice. Using loss- and gain-of-function studies in cultured human endothelial cells (ECs), we found that Gab1 depletion by siRNA augmented monocyte adhesion to ECs by increasing ICAM-1 and VCAM-1 expression in response to the proinflammatory cytokine TNF-α. Conversely, adenoviral overexpression of Gab1 inhibited TNFα-induced monocyte adhesion to ECs and upregulation of ICAM-1 and VCAM-1 in ECs. Conclusions: These results demonstrate that endothelial Gab1 represses disturbed flow-induced vascular remodeling and atherogenesis through inhibition of vascular inflammation. Our findings suggest that Gab1 activation might represent novel approaches for the treatment of vascular diseases, including intimal hyperplasia and atherosclerosis.

Direct evidence of leukocyte adhesion in arterioles by angiotensin II

Blood ◽  
2004 ◽  
Vol 104 (2) ◽  
pp. 402-408 ◽  
Author(s):  
Ángeles Álvarez ◽  
Miguel Cerdá-Nicolás ◽  
Yafa Naim Abu Nabah ◽  
Manuel Mata ◽  
Andrew C. Issekutz ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Angiotensin Ii ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Mononuclear Cells ◽  
Leukocyte Adhesion ◽  
Ang Ii ◽  
Β2 Integrin ◽  
Cell Adhesion Molecule 1

Abstract Although leukocytes adhere in arteries in various vascular diseases, to date no endogenous proinflammatory molecule has been identified to initiate leukocyte adhesion in the arterial vasculature. This study was undertaken to assess angiotensin II (Ang II)-induced leukocyte adhesion in arterioles in vivo. Rats received intraperitoneal injections of Ang II; 4 hours later, leukocyte recruitment in mesenteric microcirculation was examined using intravital microscopy. Ang II (1 nM) produced significant arteriolar leukocyte adhesion of mononuclear cells. Using function-blocking monoclonal antibodies (mAbs) against different rat cell adhesion molecules (CAMs), we discovered that this effect was dependent on P-selectin and β2-integrin. In postcapillary venules, Ang II also induced leukocyte infiltration, which was reduced by P-selectin and by β2- and α4-integrin blockade. Interestingly, neutrophils were the primary cells recruited in venules. Although β2-integrin expression in peripheral leukocytes of Ang II-treated animals was not altered, it was increased in peritoneal cells. Immunohistochemical studies revealed increased P-selectin, E-selectin, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) expression in response to Ang II in arterioles and venules. These findings provide the first evidence that Ang II causes leukocyte adhesion to the arterial endothelium in vivo at physiologically relevant doses. Therefore, Ang II may be a key molecule in cardiovascular diseases in which leukocyte adhesion to the arteries is a characteristic feature. (Blood. 2004;104:402-408)

Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver

2009 ◽  
Vol 296 (2) ◽  
pp. G147-G156 ◽  
Author(s):  
Montserrat Moreno ◽  
Leandra N. Ramalho ◽  
Pau Sancho-Bru ◽  
Marta Ruiz-Ortega ◽  
Fernando Ramalho ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Transforming Growth Factor ◽  
Inflammatory Cells ◽  
Intercellular Adhesion Molecule ◽  
Ang Ii ◽  
Beneficial Effects ◽  
Tgf Β1

Statins exert beneficial effects in chronically damaged tissues. Angiotensin II (ANG II) participates in liver fibrogenesis by inducing oxidative stress, inflammation, and transforming growth factor-β1 (TGF-β1) expression. We investigate whether atorvastatin modulates ANG II-induced pathogenic effects in the liver. Male Wistar rats were infused with saline or ANG II (100 ng·kg−1·min−1) for 4 wk through a subcutaneous osmotic pump. Rats received either vehicle or atorvastatin (5 mg·kg−1·day−1) by gavage. ANG II infusion resulted in infiltration of inflammatory cells (CD43 immunostaining), oxidative stress (4-hydroxynonenal), hepatic stellate cells (HSC) activation (smooth muscle α-actin), increased intercellular adhesion molecule (ICAM-1), and interleukin-6 hepatic gene expression (quantitative PCR). These effects were markedly blunted in rats receiving atorvastatin. The beneficial effects of atorvastatin were confirmed in an additional model of acute liver injury (carbon tetrachloride administration). We next explored whether the beneficial effects of atorvastatin on ANG II-induced actions are also reproduced at the cellular level. We studied HSC, a cell type with inflammatory and fibrogenic properties. ANG II (10−8M) stimulated cell proliferation, proinflammatory actions (NF-κB activation, ICAM-1 expression, interleukin-8 secretion) as well as expression of procollagen-α1(I) and TGF-β1. All of these effects were reduced in the presence of atorvastatin (10−7M). These results indicate that atorvastatin attenuates the pathogenic events induced by ANG II in the liver both in vivo and in vitro. Therefore, statins could have beneficial effects in conditions characterized by hepatic inflammation.

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