Osteopontin may be a driver of abdominal aortic aneurysm formation

Wang, S. Keisin; Green, Linden A.; Gutwein, Ashley R.; Gupta, Alok; Babbey, Clifford M.; Motaganahalli, Raghu L.; Fajardo, Andres; Murphy, Michael P.

doi:10.1016/j.jvs.2017.10.068

Cited by 26 publications

(23 citation statements)

References 32 publications

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“…32–34 The elaboration of cytokines such as IL-2, IFN-γ, and TNF-α by a predominantly Th1 mononuclear response stimulates pro-inflammatory osteopontin (OPN) elaboration from macrophages and vascular smooth muscle cells further propagating inflammation. 35,36 IL-6, which plays a role in maturation of lymphocytes, was also significantly elevated in our AAA population. This finding has been corroborated by recent reports; 37 additionally, blocking the IL-6R has also shown some efficacy in slowing aneurysm growth in mice.…”

Section: Discussionmentioning

confidence: 57%

Description of human AAA by cytokine and immune cell aberrations compared to risk-factor matched controls

Wang

Green

Gutwein

et al. 2018

Surgery

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Section: Discussionmentioning

confidence: 57%

Description of human AAA by cytokine and immune cell aberrations compared to risk-factor matched controls

Wang

Green

Gutwein

et al. 2018

Surgery

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“…4 Not surprisingly, in serum of patients with AAA compared with risk factor-matched non-AAA controls, we found a significant elevation in IgGs reactive to aortic-derived elastin. 5 In the inflammation stage, self-sensitized mononuclear cells hone to the infrarenal aorta, a relatively weak section of a large elastic artery prone to excessive mechanical stress secondary to the tapered configuration and shear stress introduced by the aortic bifurcation, exposing previously hidden self-antigens. 6 In addition, the infrarenal segment is relatively devoid of vascular smooth muscle cells and elastin lamellae in the tunica media, magnifying the impact of any structural damage.…”

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confidence: 99%

Immune Modulation as a Treatment for Abdominal Aortic Aneurysms

Wang

Murphy

2018

Circulation Research

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In the United States, >200 000 new patients are diagnosed with abdominal aortic aneurysm (AAA) each year. Consequently, >40 000 highly morbid aortic reconstructions are performed each year to prevent aneurysm rupture, a catastrophic event associated with near-certain mortality. No pharmaceutical currently exists to slow aneurysm growth, but a 50% reduction in diameter growth per annum could halve the number of aortic reconstructions required. Therefore, successful use of cell therapy to modulate chronic inflammation hallmark to AAA to slow diameter expansion represents a potentially paradigmaltering treatment.There continues to be no US Food and Drug-approved medication to slow or stop AAA growth. This deficit is certainly not because of a lack of effort over the previous decades. Initial investigations focused on the reduction of mechanical stress through decreasing blood pressure and sac pressurization cycles; however, clinical trials investigating drugs, such as, angiotensin II-converting enzyme inhibitors, angiotensin receptor blockers, and β-blockers, all failed to demonstrate a therapeutic reduction of diameter growth compared with placebo. Next, the inhibition of matrix metalloproteinases was trialed with doxycycline, an antibiotic inhibitor of matrix metalloproteinases 2 and 9. Doxycycline also treats species of Chlamydia, which were isolated from the aortic walls of a minority of aneurysmal arteries. Although initial uncontrolled results were promising, therapeutic response was not replicated in large randomized studies. Last, aortic wall inflammation was targeted using statins, a ubiquitous anti-inflammatory, lipid-lowering drug to limited success. The discovery of a nonsurgical treatment for AAA is contingent on the robust understanding of disease pathogenesis, which continues to be nebulous at best.AAA risk factors, such as, tobacco abuse, advancing age, uncontrolled hypertension, male sex, and white ethnicity, have all been well described but fail to provide evidence elucidating pathogenesis. Regardless, existing evidence implicates that disease initiation is multifactorial with a strong genetic element.There has been a focus of late toward the role of autoimmune mechanisms in AAA formation. The characterization of aortic wall inflammation consisting of mononuclear infiltrates, immunoglobulins, cytokines, and proteases implicate both a host innate and adaptive response. Of note, concentrations of CD4 + T cells have been recently discovered in the periadventitial vascular-associated lymphatic tissue expressing identical T cell receptors, against a currently unknown antigen, and therefore clonally expanded, providing crucial evidence for AAA as an autoimmune disease.1 Moreover, interleukin (IL)-17, a cytokine elaborated from the antigen-specific Th17 lymphocyte and overexpressed in autoimmune disorders, is highly expressed in the AAA condition. Abrogation of this cytokine, in animal models, has demonstrated efficacy in decreasing aneurysm diameter growth.2 Although several putative autoantigens have b...

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“…Ponadto OPN, podobnie jak Hcy, jest zaangażowana w rozwój choroby miażdżycowej i proteolizę. Nasila więc degenerację w ścianie aorty [23]. Osteopontyna jest wydzielana w odpowiedzi na stres przez osteoblasty, makrofagi, a w ścianie naczyń krwionośnych przez komórki mięśni gładkich oraz śródbłonka.…”

Section: Aorty Brzusznejunclassified

“…Regulacja jej ekspresji odgrywa kluczową rolę w migracji makrofagów i komórek mięśni gładkich, co jest ściśle powiązane z przebudową naczyń oraz rozwojem choroby miażdżycowej. Stężenie OPN w osoczu wiąże się ściśle z rozwojem chorób układu sercowo-naczyniowego, w tym AAA [23,24].…”

Section: Aorty Brzusznejunclassified

Czynniki charakterystyczne dla tętniaka aorty brzusznej i jego potencjalne biomarkery

Stępień

Lesiak

Sieroń

2019

Choroby Serca I Naczyń

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Tętniak aorty brzusznej (AAA) jest schorzeniem wieloczynnikowym i bezobjawowym, charakteryzującym się wysoką śmiertelnością pacjentów. Istnieje wiele indukujących go czynników, ale do tej pory nie zidentyfikowano jednego kluczowego, o podłożu molekularnym, genetycznym czy środowiskowym, który przyczynia się do powstania tętniaka. Uszkodzenie struktury macierzy zewnątrzkomórkowej, apoptoza komórek mięśni gładkich ściany naczynia i komórek śródbłonkowych poprzez czynniki degeneracyjne indukuje proces tworzenia tętniaka w ścianie naczynia. Towarzyszy temu postępujący proces zapalny. Badaniem pozwalającym na wykrycie AAA jest ultrasonografia jamy brzusznej. Nie jest to jednak rutynowe badanie przesiewowe wykonywane u wszystkich osób, dlatego do zdiagnozowania AAA dochodzi w bardzo zaawansowanym stadium choroby, co zagraża życiu pacjenta. Jedynym medycznym postępowaniem w tym przypadku pozostaje zabieg chirurgiczny, dlatego koniecznym wydaje się poznanie procesów molekularnych, biomarkerów AAA oraz genów odpowiedzialnych za mechanizm powstawania tętniaków. Umożliwiłoby to szybszą i efektywniejszą diagnostykę, a tym samym zapoczątkowałoby proces leczenia.

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Osteopontin may be a driver of abdominal aortic aneurysm formation

Abstract: OPN, secreted by the VSMCs of the tunica media, is elevated in the circulating plasma and aortic wall of patients with AAA. It can inhibit the induction of the TR1 suppressor cell, leading to an overall proinflammatory state contributing to progressive aortic wall breakdown and dilation.

Cited by 26 publications

References 32 publications

Description of human AAA by cytokine and immune cell aberrations compared to risk-factor matched controls

Description of human AAA by cytokine and immune cell aberrations compared to risk-factor matched controls

Immune Modulation as a Treatment for Abdominal Aortic Aneurysms

Czynniki charakterystyczne dla tętniaka aorty brzusznej i jego potencjalne biomarkery

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