Angiotensin II Increases Macrophage-mediated Modification of Low Density Lipoprotein via a Lipoxygenase-dependent Pathway

Scheidegger, Kathrin J.; Butler, Susan; Witztum, Joseph L.

doi:10.1074/jbc.272.34.21609

Cited by 122 publications

(69 citation statements)

References 52 publications

(48 reference statements)

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“…24 -26 Ang II promotes recruitment of inflammatory cells to the vessel wall by inducing the expression of monocyte chemoattractant protein-1. 27 Ang II increases low-density lipoprotein oxidation 28 and by interacting with the Ang II subtype-1 (AT1) receptor on macrophage increases 12/15-lipoxygenase activity, 29 suggesting that it may exacerbate atherosclerosis. Indeed, the present study also demonstrated that Ang II exacerbates atherosclerosis in apoE-KO mice.…”

Section: Discussionmentioning

confidence: 99%

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

Wang¹,

Martin-McNulty²,

Freay

et al. 2001

The American Journal of Pathology

111

125

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Urokinase-type plasminogen activator (uPA) is increased in human abdominal aortic aneurysm (AAA).Chronic infusion of angiotensin II (Ang II) results in AAA in apolipoprotein E-deficient mice. We tested the hypothesis that Ang II infusion results in an elevation of uPA expression contributing to aneurysm formation. Ang II or vehicle was infused by osmotic pumps into apoE-KO mice. All mice treated with Ang II developed a localized expansion of the suprarenal aorta (75% increase in outer diameter), accompanied by an elevation of blood pressure (22 mmHg), compared to the vehicle-treated group. Histological examination of the dilated aortic segment revealed similarities to human AAA including focal elastin fragmentation, macrophage infiltration, and intravascular hemorrhage. Ang II treatment resulted in a 13-fold increase in the expression of uPA mRNA in the AAA segment in contrast to a twofold increase in the atherosclerotic aortic arch. Increased uPA protein was detected in the abdominal aorta as early as 10 days after Ang II infusion before significant aorta expansion. Thus, Ang II infusion results in macrophage infiltration, increased uPA activity, and aneurysm formation in the abdominal aorta of apoE-KO mice. These data are consistent with a causal role for uPA in the pathogenesis of AAA. Abdominal aortic aneurysm (AAA) is a chronic degenerative disease characterized by segmental weakening and dilation of the vascular wall. Recent estimates indicate that the prevalence of AAA is 4 to 9% in adults older than 65 years of age and is known to be associated with atherosclerosis, aging, hypertension, and cigarette smoking. Continued tissue remodeling results in silent expansion of the AAA with an increased risk of spontaneous rupture. Currently the only available treatments for AAAs are surgical resection and replacement or, more recently, insertion of an endovascular stent. The etiology of AAA is unclear. The extracellular matrix plays an essential role in maintaining the integrity of the vascular wall. Elastin and collagen fibers are the major components of this extracellular matrix. Both plasmin and matrix metalloproteinases (MMPs) are capable of degrading extracellular matrix, including collagen, elastin, and fibrin. Urokinase-type plasminogen activator (uPA) hydrolyzes plasminogen to form plasmin, which in turn activates MMPs. The in vivo activity of uPA is also regulated by local concentrations of its major inhibitor, PAI-1. Biochemical studies have demonstrated increased proteolytic activity in the aortic wall of AAA. Schneiderman and colleagues 1 showed that uPA mRNA as well as the tissue-type plasminogen activator (tPA), co-localized with infiltrating macrophages, is significantly increased in human AAA. Increased activities of MMP-2, -3, -9, and -12 in AAA have also been reported. [2][3][4][5] Atherosclerotic aortic lesions from high-cholesterol diet-fed apoE-KO mice show fragmentation of the elastic lamellae and rupture of the media resulting in pseudomicroaneurysm formation. These pathological changes are ...

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Section: Discussionmentioning

confidence: 99%

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

Wang¹,

Martin-McNulty²,

Freay

et al. 2001

The American Journal of Pathology

111

125

View full text Add to dashboard Cite

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“…38 There is evidence that the lipoxygenase pathway is a mediator of angiotensin II, implicating a role for humoral factors such as angiotensin II in mediating oxidative stress responses in the vessel wall. 39 Thus, activation of lipoxygenase may be a possible mechanism contributing to formation of lipid peroxides and oxysterols. Because probucol was able to inhibit cholesterol oxidation in hypertensive rabbits, this finding provides further evidence for continued studies on peroxidation-mediated vascular effects in hypertensive animals.…”

Section: Discussionmentioning

confidence: 99%

Probucol Reduces Oxysterol Formation in Hypertensive Rabbits

et al. 2000

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Abstract-The role of lipid peroxidation during the pathogenesis of atherosclerosis has been described through numerous studies and has provided compelling evidence for free radical-mediated processes that link hypertension with atherosclerosis. However, there remains only limited information concerning peroxidative processes in hypertension and their modulation by antioxidants. In the present study, the formation of cholesterol oxidation products was used as a measure of in vivo lipid peroxidation after hypertension induced by coarctation of the aorta in New Zealand White rabbits. The rabbits were fed a standard chow diet devoid of cholesterol or cholesterol oxidation products such that the measured cholesterol oxides in the plasma and aortic tissues would most plausibly arise from endogenous oxidation of cholesterol. After 12 weeks of hypertension, all of the measured cholesterol oxides increased significantly over baseline levels in the surgically coarctated animals; however, this increase was significantly less in hypertensive probucol-treated animals. Similarly, the cholesterol oxide content of aortic tissue from the surgically coarctated animals was significantly greater than that found in normotensive control aortas, and probucol treatment significantly reduced the increase in cholesterol oxide content of aortic tissue relative to that of hypertensive animals not receiving the antioxidant. These findings in hypertensive animals suggest that cholesterol oxidation products measured in plasma and aortic tissue can be derived from endogenous free radical activity and that this activity is enhanced under specific pathological conditions. (Hypertension. 2000;36:436-441.)

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“…Nitric oxide can inhibit transglutaminase activity through nitrosylation of the active-site cysteine (Bernassola et al, 1999;Catani et al, 1998;Melino et al, 1997) or through the reaction of nitric oxide with O 2 է to form peroxynitrite, because cysteine residues are particularly sensitive to oxidation with peroxynitrite (Berlett and Stadtman, 1997). Thus, the generation of oxidant stress from smoking (Pryor et al, 1984;Tully et al, 1969), hyperlipidemia (Ohara et al, 1993), diabetes (Horie et al, 1997;Schmidt et al, 1995), and hypertension (Harrison, 1997;Scheidegger et al, 1997), as well as the health status of the endothelium, which is influenced by these and other risk factors (Harrison, 1997), could modulate TG activity.…”

Section: Tg In Atherosclerosismentioning

confidence: 99%

Localization of Tissue Transglutaminase in Human Carotid and Coronary Artery Atherosclerosis: Implications for Plaque Stability and Progression

Haroon

Wannenburg

Gupta

et al. 2001

Laboratory Investigation

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SUMMARY:Although atherosclerosis progresses in an indolent state for decades, the rupture of plaques creates acute ischemic syndromes that may culminate in myocardial infarction and stroke. Mechanical forces and matrix metalloproteinase activity initiate plaque rupture, whereas tissue inhibitors of metalloproteinases have an important (albeit indirect) role in plaque stabilization. In this paper, an enzyme that could directly stabilize the plaque is described. Tissue transglutaminase (TG) catalyzes the formation of ⑀(␥-glutamyl)lysine isopeptide bonds that are resistant to enzymatic, mechanical, and chemical degradation. We performed immunohistochemistry for TG in atherosclerotic human coronary and carotid arteries. TG was most prominent along the luminal endothelium and in the medium of the vessels with a distribution mirroring that of smooth muscle cells. Variable, often prominent, immunoreactivity for TG was also seen in the intima, especially in regions with significant neovascularization. Additionally, TG was detected in fibrous caps and near the "shoulder regions" of some plaques. A monoclonal antibody to the transglutaminase product ⑀(␥-glutamyl)lysine isopeptide demonstrated co-localization with TG antigen. Transglutaminase activity was found in 6 of 14 coronary artery atherectomy samples. Cross-linking of TG substrates such as fibrinogen, fibronectin, vitronectin, collagen type I, and protease inhibitors stabilized the plaque. Furthermore, the activation of transforming growth factor-beta-1 by TG might be an additional mechanism for the promotion of plaque stabilization and progression by increasing the synthesis of extracellular matrix components. (Lab Invest 2001, 81:83-93).

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Angiotensin II Increases Macrophage-mediated Modification of Low Density Lipoprotein via a Lipoxygenase-dependent Pathway

Cited by 122 publications

References 52 publications

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

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

Probucol Reduces Oxysterol Formation in Hypertensive Rabbits

Localization of Tissue Transglutaminase in Human Carotid and Coronary Artery Atherosclerosis: Implications for Plaque Stability and Progression

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