Inhibition of cyclooxygenase with indomethacin phenethylamide reduces atherosclerosis in apoE-null mice

Burleigh, Michael E.; Babaev, Vladimir R.; Patel, Mayur B.; Crews, Brenda C.; Morrow, Jason D.; Oates, John A.; Marnett, Lawrence J.; Fazio, Sergio; Linton, MacRae F.

doi:10.1016/j.bcp.2005.04.044

Cited by 14 publications

(5 citation statements)

References 38 publications

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“…9 As in humans, mouse and rabbit models of atherosclerosis have COX-2 expression in fatty streaks and atherosclerotic vessels. 8,15,52,98,113 These data indicate that in animal models of atherosclerosis, the expression of COX isoforms is similar to that of humans.…”

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confidence: 71%

Pathophysiology of Cyclooxygenases in Cardiovascular Homeostasis

2010

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Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid into prostaglandin H(2) (PGH(2)), which is subsequently converted to the prostanoids PGE(2), PGI(2), PGF(2alpha), and thromboxane A(2). COX has 2 distinct membrane-anchored isoenzymes: COX-1 and COX-2. COX-1 is constitutively expressed in most normal tissues; COX-2 is highly induced by proinflammatory mediators in the setting of inflammation, injury, and pain. Inhibitors of COX activity include conventional nonselective nonsteroidal anti-inflammatory drugs and selective nonsteroidal anti-inflammatory drugs, such as COX-2 inhibitors. The adverse effects of COX inhibitors on the cardiovascular system have been addressed in the last few years. In general, COX inhibitors have many effects, but those most important to the cardiovascular system can be direct (through the effects of prostanoids) and indirect (through alterations in fluid dynamics). Despite reports of detrimental human cardiovascular events associated with COX inhibitors, short, long, and lifetime preclinical toxicology studies in rodents and nonrodents have failed to identify these risks. This article focuses on the expression and function of COX enzymes in normal and pathologic conditions of the cardiovascular system and discusses the cardiovascular pathophysiologic complications associated with COX inhibition.

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confidence: 71%

Pathophysiology of Cyclooxygenases in Cardiovascular Homeostasis

2010

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“…Thus, given its known proinflammatory characteristics (2,4,23), HHcy may also contribute to the proinflammatory response in C57BL/6J mice fed the A diet, thereby acting in concert with VLDL to accelerate atherosclerotic lesion development. Al-though anti-inflammatories such as curcumin (44), resveratrol (45), indomethacin (46) or statins (47-49) reduce atherosclerosis in apoE −/− mice, further experiments are necessary to determine whether treatment with antiinflammatories can reduce atherogenesis in C57BL/6J mice fed the A or A + M diet.…”

Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinemia induced by methionine supplementation does not independently cause atherosclerosis in C57BL/6J mice

Zhou¹,

Werstuck²,

Lhoták³

et al. 2008

FASEB j.

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A causal relationship between diet-induced hyperhomocysteinemia (HHcy) and accelerated atherosclerosis has been established in apolipoprotein E-deficient (apoE −/− ) mice. However, it is not known whether the proatherogenic effect of HHcy in apoE −/− mice is independent of hyperlipidemia and/or deficiency of apoE. In this study, a comprehensive dietary approach using C57BL/6J mice was used to investigate whether HHcy is an independent risk factor for accelerated atherosclerosis or dependent on additional dietary factors that increase plasma lipids and/or inflammation. C57BL/ 6J mice at 4 wk of age were divided into 6 dietary groups: chow diet (C), chow diet + methionine (C+M), western-type diet (W), western-type diet + methionine (W+M), atherogenic diet (A), or atherogenic diet + methionine (A+M). After 2, 10, 20, or 40 wk on the diets, mice were sacrificed, and the levels of total plasma homocysteine, cysteine, and glutathione, as well as total plasma cholesterol and triglycerides were analyzed. Aortic root sections were examined for atherosclerotic lesions. HHcy was induced in all groups supplemented with methionine, compared to diet-matched control groups. Plasma total cholesterol was significantly increased in mice fed the W or A diet. However, the W diet increased LDL/IDL and HDL levels, while the A diet significantly elevated plasma VLDL and LDL/IDL levels without increasing HDL. No differences in plasma total cholesterol levels or lipid profiles were observed between methionine-supplemented groups and the diet-matched control groups. Early atherosclerotic lesions containing macrophage foam cells were only observed in mice fed the A or A + M diet. Furthermore, lesion size was significantly larger in the A + M group compared to the A group at 10 and 20 wk; however, mature lesions were never observed even after 40 wk on these diets. The presence of lymphocytes, increased hyaluronan staining, and the expression of endoplasmic reticulum (ER) stress markers were also increased in atherosclerotic lesions from the A + M group. Taken together, these results suggest that HHcy does not independently cause atherosclerosis in C57BL/6J mice even in the presence of increased total Clinical and epidemiological studies have established that elevated plasma total homocysteine (tHcy) is an independent risk factor for cardiovascular disease and stroke (1,2). Furthermore, accelerated atherosclerosis has been demonstrated in apolipoprotein E-deficient (apoE −/− ) mice with dietary hyperhomocysteinemia (HHcy) (3-5) and in cystathionine β-synthase (CBS)/apoE −/− double-knockout mice (6). These findings suggest that HHcy accelerates atherogenesis in a hyperlipidemic mouse model that develops spontaneous atherosclerosis. However, a causal relationship between atherogenesis and HHcy has not been established in other species, including rats, rabbits, pigs, and primates (7-10).Patients with inborn errors of methionine metabolism due to deficiencies in CBS or 5,10-methylenetetrahydrofolate reductase (MTHFR) present with severe...

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“…Whereas some preclinical data incriminate COX-2 activity as deleterious and proatherogenic (5)(6)(7), others (11,12,29) support the protective role of PGI 2 in atherogenic conditions. To increase the level of complexity, oxidative stress favors the expression of an inflammatory phenotype that leads to the induction of COX-2 (11,22,29).…”

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confidence: 99%

Aging associated with mild dyslipidemia reveals that COX-2 preserves dilation despite endothelial dysfunction

Gendron

Thorin‐Trescases²,

Villeneuve³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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The endothelial function declines with age, and dyslipidemia (DL) has been shown to hasten this process by favoring the generation of reactive oxygen species (ROS). Cyclooxygenase-2 (COX-2) can be induced by ROS, but its contribution to the regulation of the endothelial function is unknown. Since COX-2 inhibitors may be deleterious to the cardiovascular system, we hypothesized that DL leads to ROS-dependent endothelial damage and a protective upregulation of COX-2. Dilations to acetylcholine (ACh) of renal arteries isolated from 3-, 6-, and 12-mo-old wild-type (WT) and DL mice expressing the human ApoB-100 were recorded with or without COX inhibitors and the antioxidant N-acetyl-l-cystein (NAC). Nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) were inhibited using N(omega)-nitro-l-arginine (l-NNA) and a depolarizing solution, respectively. In WT mice, the dilation to ACh declined at 12 mo but was insensitive to COX-1/2 inhibition alone or with NAC. DL led to an early endothelial dysfunction at 6 mo, normalized, however, by NAC. At 12 mo, vascular sensitivity to ACh was further reduced by DL. At this age, selective COX-2 inhibition reduced the dilation, whereas addition of NAC improved it. In 3- and 6-mo-old WT mice, l-NNA significantly reduced the dilation, whereas it limited the dilation only in 3-mo-old DL mice. EDHF-dependent dilation remains identical in both groups. These data suggest that COX-2 activity confers endothelium-dependent vasodilatory function in aged DL mice in the face of a pro-oxidative environment. Upregulation of this pathway compensates for the early loss of the contribution of NO in DL mice.

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Inhibition of cyclooxygenase with indomethacin phenethylamide reduces atherosclerosis in apoE-null mice

Cited by 14 publications

References 38 publications

Pathophysiology of Cyclooxygenases in Cardiovascular Homeostasis

Pathophysiology of Cyclooxygenases in Cardiovascular Homeostasis

Hyperhomocysteinemia induced by methionine supplementation does not independently cause atherosclerosis in C57BL/6J mice

Aging associated with mild dyslipidemia reveals that COX-2 preserves dilation despite endothelial dysfunction

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