Role of Oxidative Stress in the Pathogenesis of Abdominal Aortic Aneurysms

McCormick, Michael L.; Gavrila, Dan; Weintraub, Neal L.

doi:10.1161/01.atv.0000257552.94483.14

Cited by 296 publications

(261 citation statements)

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“…Oxidative stress has been described as an important signaling pathway in human AAA development and animal models of AAA 21, 22. The specific identity of reactive oxygen species that is responsible for the development of aortic dilation remains elusive 4, 23, 24. Here, we investigate the effect of vascular peroxidase 1 (VPO1), a newly identified heme‐containing peroxidase is primarily expressed in cardiovascular system,25 on VSMC phenotypic switch, which is the early stages of aortic aneurysms formation.…”

Section: Discussionmentioning

confidence: 99%

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VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

Peng

Zhang

Liu

et al. 2018

JAHA

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BackgroundHydrogen peroxide (H2O2) is a critical molecular signal in the development of abdominal aortic aneurysm (AAA) formation. Vascular peroxidase 1 (VPO1) catalyzes the production of hypochlorous acid (HOCl) from H2O2 and significantly enhances oxidative stress. The switch from a contractile phenotype to a synthetic one in vascular smooth muscle cells (VSMCs) is driven by reactive oxygen species and is recognized as an early and important event in AAA formation. This study aims to determine if VPO1 plays a critical role in the development of AAA by regulating VSMC phenotypic switch.Methods and Results VPO1 is upregulated in human and elastase‐induced mouse aneurysmal tissues compared with healthy control tissues. Additionally, KLF4, a nuclear transcriptional factor, is upregulated in aneurysmatic tissues along with a concomitant downregulation of differentiated smooth muscle cell markers and an increase of synthetic phenotypic markers, indicating VSMC phenotypic switch in these diseased tissues. In cultured VSMCs from rat abdominal aorta, H2O2 treatment significantly increases VPO1 expression and HOCl levels as well as VSMC phenotypic switch. In support of these findings, depletion of VPO1 significantly attenuates the effects of H2O2 and HOCl treatment. Furthermore, HOCl treatment promotes VSMC phenotypic switch and ERK1/2 phosphorylation. Pretreatment with U0126 (a specific inhibitor of ERK1/2) significantly attenuates HOCl‐induced VSMC phenotypic switch.ConclusionsOur results demonstrate that VPO1 modulates VSMC phenotypic switch through the H2O2/VPO1/HOCl/ERK1/2 signaling pathway and plays a key role in the development of AAA. Our findings also implicate VPO1 as a novel signaling node that mediates VSMC phenotypic switch and plays a key role in the development of AAA.Clinical Trial Registration URL: http://www.chictr.org.cn. Unique identifier: ChiCTR1800016922.

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Section: Discussionmentioning

confidence: 99%

“…Oxidative stress plays a critical role in AAA formation and has also been implicated in regulating VSMC phenotypic switch 4. Hydrogen peroxide (H 2 O 2 ), an important reactive oxygen species, acts as a key signaling molecule that modulates VSMCs growth, differentiation, and migration 5.…”

Section: Introductionmentioning

confidence: 99%

VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

Peng

Zhang

Liu

et al. 2018

JAHA

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“…The activation of MMPs is associated with increased oxidative stress. 18,38 We have previously reported that Ang II generates ROSs from arachidonic acid via CYP1B1. 11 CYP1B1 can metabolize various substrates, including steroids, retinoic acid, and fatty acids.…”

Section: Discussionmentioning

confidence: 99%

“…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. 38,55 Whether oxidative stress generated by Ang II through CYP1B1 increases COX-2 expression in a parallel manner or sequential pathway remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…Ang II increases COX-2 expression in VSMCs via p38 mitogen-activated protein kinase, 37 and this pathway been implicated in the pathogenesis of AAA. 38 Therefore, we determined the contribution of CYP1B1 to the expression of COX-2 in Ang IIeinduced AAA. Ang II infusion increased COX-2 expression in aortic sections of Apoe À/À / Cyp1b1 þ/þ mice, which was attenuated by TMS treatment, and in Apoe À/À /Cyp1b1 À/À mice ( Figure 5, E and F).…”

Section: Tms or Cyp1b1 Gene Disruption Minimizes Increases In Aortic mentioning

confidence: 99%

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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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A Multi‐Bioactive Nanomicelle‐Based “One Stone for Multiple Birds” Strategy for Precision Therapy of Abdominal Aortic Aneurysms

et al. 2022

Advanced Materials

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AAAs are characterized by the abdominal aortic diameter ≥3 cm or having ≥50% increase in the largest diameter of the abdominal aorta. [3] The estimated prevalence of AAA is 4-8% among people over 65 years old. [3b,4] Most individuals with AAAs are asymptomatic, but rupture of AAA results in mortality as high as 90%. [3a,5] Therefore, AAA is a serious and lethal aortic disease. The natural process of AAA is implicated by the continuous enlargement of the infrarenal aorta, and the turbulent blood flow in the aortic lumen promotes the formation of intraluminal thrombus. [3,6] Once the aneurysm diameter is larger than 5.5 cm, the risk of AAA rupture remarkably increases. [3b] Thus far, surgical intervention, including open surgery and endovascular aneurysm repair (EVAR), remains the only available choice for effective management of AAA. [7] Nevertheless, the surgical intervention of AAA has shown various post-operative complications, such as infection, [8] endoleak, [9] cardiopulmonary events, [10] acute kidney injury [11] and spinal cord injury. [2,12] Moreover, ≈20-30% patients require re-intervention after surgery owing to reperfusion and associated secondary aneurysm rupture, leading to reduced patient compliance as well as increased surgical risk and mortality. [2,3] Besides, surgical treatment is not suitable for Abdominal aortic aneurysm (AAA) remains a lethal aortic disease in the elderly. Currently, no effective drugs can be clinically applied to prevent the development of AAA. Herein, a "one stone for multiple birds" strategy for AAA therapy is reported. As a proof of concept, three bioactive conjugates are designed and synthesized, which can assemble into nanomicelles. Cellularly, these nanomicelles significantly inhibit migration and activation of inflammatory cells as well as protect vascular smooth muscle cells (VSMCs) from induced oxidative stress, calcification and apoptosis, with the best effect for nanomicelles (TPTN) derived from a conjugate defined as TPT. After intravenous delivery, TPTN efficiently accumulates in the aneurysmal tissue of AAA rats, showing notable distribution in neutrophils, macrophages and VSMCs, all relevant to AAA pathogenesis. Whereas three examined nanomicelles effectively delay expansion of AAA in rats, TPTN most potently prevents AAA growth by simultaneously normalizing the pro-inflammatory microenvironment and regulating multiple pathological cells. TPTN is effective even at 0.2 mg kg −1 . Besides, TPTN can function as a bioactive nanoplatform for site-specifically delivering and triggerably releasing anti-aneurysmal drugs, affording synergistic therapeutic effects. Consequently, TPTN is a promising multi-bioactive nanotherapy and bioresponsive targeting delivery nanocarrier for effective therapy of AAA and other inflammatory vascular diseases.

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Role of Oxidative Stress in the Pathogenesis of Abdominal Aortic Aneurysms

Cited by 296 publications

References 103 publications

VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

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

A Multi‐Bioactive Nanomicelle‐Based “One Stone for Multiple Birds” Strategy for Precision Therapy of Abdominal Aortic Aneurysms

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