Genetic deficiency of cyclooxygenase-2 attenuates abdominal aortic aneurysm formation in mice

Gitlin, Jonathan M.; Trivedi, Darshini B.; Langenbach, Robert; Loftin, Charles D.

doi:10.1016/j.cardiores.2006.10.015

Cited by 74 publications

(75 citation statements)

References 43 publications

(68 reference statements)

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“…37,54 Our results demonstrating that an increase in COX-2 expression in Ang IIeinduced AAA in Apoe À/À /Cyp1b1 þ/þ mice was prevented by TMS or Cyp1b1 gene disruption suggests that CYP1B1 acts upstream of COX-2 in minimizing AAA, which could be due to ROSs generated by CYP1B1. Supporting this view was our finding that the administration of tempol attenuated the expression of COX-2, which could occur via p38 MAPK, as reported in previous studies.…”

Section: Discussionmentioning

confidence: 86%

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Thirunavukkarasu

Khan

Song

et al. 2016

The American Journal of Pathology

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Cytochrome P450 (CYP) 1B1 is implicated in vascular smooth muscle cell migration, proliferation, and hypertension. We assessed the contribution of CYP1B1 to angiotensin (Ang) IIeinduced abdominal aortic aneurysm (AAA). Male Apoe À/À /Cyp1b1 þ/þ and Apoe À/À /Cyp1b1 À/À mice were infused with Ang II or its vehicle for 4 weeks; another group of Apoe À/À /Cyp1b1 þ/þ mice was coadministered the CYP1B1 inhibitor 2,3 0 ,4,5 0 -tetramethoxystilbene (TMS) every third day for 4 weeks. On day 28 of Ang II infusion, AAAs were analyzed by ultrasound and ex vivo by Vernier calipers, mice were euthanized, and tissues were harvested. Ang II produced AAAs in Apoe À/À /Cyp1b1 þ/þ mice; mice treated with TMS or Apoe À/À /Cyp1b1 À/À mice had reduced AAAs. Ang II enhanced infiltration of macrophages, T cells, and platelets and increased plateletderived growth factor D, Pdgfrb, Itga2, and matrix metalloproteinases 2 and 9 expression in aortic lesions; these changes were inhibited in mice treated with TMS and in Apoe À/À /Cyp1b1 À/À mice. Oxidative stress resulted in cyclooxygenase-2 expression in aortic lesions. These effects were minimized in Apoe À/À / Cyp1b1 þ/þ mice treated with TMS and in Apoe À/À /Cyp1b1 À/À mice and by concurrent treatment with the superoxide scavenger 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl. CYP1B1 contributed to the development of Ang IIeinduced AAA and associated pathogenic events in mice, likely by enhancing oxidative stress and associated signaling events. Thus, CYP1B1 may serve as a target for therapeutic agents for AAA in males. (Am J Pathol 2016 http://dx

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Section: Discussionmentioning

confidence: 86%

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Thirunavukkarasu

Khan

Song

et al. 2016

The American Journal of Pathology

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“…3 Inflammatory cells produce proinflammatory cytokines and interlace an inflammatory network, which may contribute to tissue destruction and weakened arterial wall. 4 Matrix metalloproteinases (MMPs), expecially MMP-2 and MMP-9, the predominant proteinases in the aortic wall, degrade the extracellular matrix (ECM) and are thought to play a key role in AAA formation. 5 Experimental evidence has emerged that defective inflammation and inhibition of MMP activity may attenuate aneurysm formation in animal models.…”

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confidence: 99%

Regulatory T Cells Prevent Angiotensin II–Induced Abdominal Aortic Aneurysm in Apolipoprotein E Knockout Mice

et al. 2014

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To test the hypothesis that adoptive transfer of regulatory T cells (Tregs) may dose-dependently inhibit the formation of angiotensin II–induced abdominal aortic aneurysm in apolipoprotein E knockout mice, we established an animal model of abdominal aortic aneurysm by angiotensin II infusion in apolipoprotein E knockout mice. Then mice received different treatment with PBS, low-dose Tregs, high-dose Tregs, or CD25-depleting PC61 antibody. Histopathologic analysis showed that the incidence of abdominal aortic aneurysm was 80%, 76%, 27%, and 71% in the PBS, low-dose Tregs, high-dose Tregs, and PC61 groups, respectively. Tregs treatment markedly decreased macrophage and CD4 + T-cell infiltration and preserved the medial smooth muscle cells. Furthermore, Tregs decreased the levels of proinflammatory cytokines, matrix metalloproteinase-2 (MMP-2) and MMP-9, increased the expression of anti-inflammatory interleukin-10 and transforming growth factor-β, and suppressed apoptosis and oxidative stress. In vitro, Tregs inhibited the response of human aortic smooth muscle cells to angiotensin II and reduced the expression of proinflammatory cytokines, MMP-2 and MMP-9, possibly by inhibiting the activation of nuclear factor-κB and extracellular signal-regulate kinase 1/2. In addition, Tregs downregulated macrophage type 1–related genes and upregulated macrophage type 2–related genes. However, Tregs-mediated effects were largely reversed by disrupting cell–cell contact or using neutralizing antibodies against interleukin-10 and transforming growth factor-β. Adoptive transfer of Tregs dose-dependently prevents angiotensin II–induced abdominal aortic aneurysm in apolipoprotein E knockout mice. The mechanisms may involve declined proinflammatory cytokine expression and MMP-2 and MMP-9 levels and enhanced anti-inflammatory cytokine expression, which is mediated by direct cell–cell contact and soluble mediators.

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“…Moreover, Ang II may stimulate the expression of cyclooxygenase-2 (COX-2) [42,43], a critical enzyme in AAA pathogenesis that forms vasoactive and inflammatory prostaglandins. Indeed, it has been shown that COX-2 deficiency attenuates Ang II infusion-mediated dissecting AAA [44]. Ang II also may stimulate osteopontin (OPN) secretion and actions [45].…”

Section: Renin Angiotensin System -Classical Systemmentioning

confidence: 99%

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

Fraga‐Silva

Trachet²,

Stergiopulos³

2015

CPD

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Abdominal aortic aneurysm (AAA) is a local expansion of the abdominal aorta wall caused by a complex multifactorial maladaptive vascular remodeling. Despite recent advances in the management of cardiovascular diseases, there currently is no established drug therapy for AAA. Since the probability of death from a ruptured AAA still remains high, preventive elective repair of AAAs larger than 5.5 cm in luminal diameter is considered the best treatment option. However, perioperative complications are problematic as elective AAA repair comes with numerous intrinsic risks. Impelled by the need of improving AAA therapy, significant efforts have been made to identify pharmacological tools that would slow down AAA enlargement and lower the risk of rupture, thereby reducing the necessity of surgical intervention. In this review, we discuss recent findings addressing molecular targets that could potentially treat AAA, particularly addressing: statins, classical renin angiotensin system (RAS) blockers, the protective arm of RAS, renin inhibitors, tetracyclines, interleukin-1β inhibition, anti-angiogenic agents and urocortins.

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Genetic deficiency of cyclooxygenase-2 attenuates abdominal aortic aneurysm formation in mice

Abstract: Our findings suggest that increased COX-2 expression in smooth muscle cells of the abdominal aorta contributes to AAA formation in mice by enhancing inflammatory cell infiltration.

Cited by 74 publications

References 43 publications

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Regulatory T Cells Prevent Angiotensin II–Induced Abdominal Aortic Aneurysm in Apolipoprotein E Knockout Mice

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

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