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Inflammation in thoracic aortic aneurysms

Entzündungsprozesse bei thorakalen Aortenaneurysmen

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Abstract

Mutations in extracellular matrix and smooth muscle cell contractile proteins predispose to thoracic aortic aneurysms in Marfan syndrome (MFS) and related disorders. These genetic alterations lead to a compromised extracellular matrix–smooth muscle cell contractile unit. The abnormal aortic tissue responds with defective mechanosensing under hemodynamic stress. Aberrant mechanosensing is associated with transforming growth factor-beta (TGF-β) hyperactivity, enhanced angiotensin-II (Ang-II) signaling, and perturbation of other cellular signaling pathways. The downstream consequences include enhanced proteolytic activity, expression of inflammatory cytokines and chemokines, infiltration of inflammatory cells in the aortic wall, vascular smooth muscle cell apoptosis, and medial degeneration. Mouse models highlight aortic inflammation as a contributing factor in the development of aortic aneurysms. Anti-inflammatory drugs and antioxidants can reduce aortic oxidative stress that prevents aggravation of aortic disease in MFS mice. Targeting TGF-β and Ang-II downstream signaling pathways such as ERK1/2, mTOR, PI3/Akt, P38/MAPK, and Rho kinase signaling attenuates disease pathogenesis. Aortic extracellular matrix degradation and medial degeneration were reduced upon inhibition of inflammatory cytokines and matrix metalloproteinases, but the latter lack specificity. Treating inflammation associated with aortic aneurysms in MFS and related disorders could prove to be beneficial in limiting disease pathogenesis.

Zusammenfassung

Mutationen in Proteinen der extrazellulären Matrix (EZM) und von glatten Muskelzellen der Aorta prädisponieren zu thorakalen Aortenaneurysmen beim Marfan-Syndrom (MFS) und verwandten Erkrankungen. Diese genetischen Veränderungen führen zu einer Schädigung der kontraktilen Einheit aus EZM und glatten Muskelzellen. Das veränderte Aortengewebe reagiert mit einem defekten „mechanosensing“ (Reaktionsverhalten auf mechanische Reize) der Zelle unter hämodynamischem Stress. Das aberrante „mechanosensing“ ist mit Überaktivierung von TGF-β, verstärktem Angiotensin-II(Ang-II)-Signaling und Störungen von anderen zellulären Signalwegen assoziiert. Hierdurch kommt es zu einer verstärkten proteolytischen Aktivität, Expression inflammatorischer Zytokine und Chemokine, Einwanderung inflammatorischer Zellen in die Gefäßwand, Apoptose glatter Muskelzellen und Degeneration der Media. Mausmodelle belegen, dass eine Entzündung der Aorta ein relevanter Faktor in der Pathogenese von Aortenaneurysmen ist. Antiinflammatorische Medikamente und Antioxidanzien können den oxidativen Stress reduzieren, der zur Verschlechterung der pathologischen Veränderungen der Aorta bei MFS-Mäusen führt. Die Hemmung von Komponenten der TGF-β- und Ang-II-Signalwege (ERK1/2, mTOR, PI3/Akt, P38/MAPK, Rho-Kinase) verbessert den Verlauf der Erkrankung. Der Abbau der EZM in der Aorta und die Degeneration der Media können durch Inhibitoren von inflammatorischen Zytokinen und Matrixmetalloproteasen reduziert werden, Letztere weisen jedoch keine ausreichende Spezifität auf. Die Behandlung von Entzündungsprozessen der Aorta, die beim MFS und bei verwandten Erkrankungen mit der Ausbildung von Aneurysmen assoziiert sind, könnte sich daher als vorteilhaft erweisen, um ein Fortschreiten der Erkrankung zu verlangsamen.

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Abbreviations

Ang-II:

Angiotensin-II

AT1R:

Angiotensin type-1 receptor

ECM:

Extracellular matrix

ERK1/2:

Extracellular signal-regulated kinase 1/2

IL:

Interleukin

JNK:

C-Jun N‑terminal kinase

MCP-1:

Macrophage chemotactic protein-1

M-CSF:

Macrophage colony-stimulating factor

MFS:

Marfan syndrome

MMP:

Matrix metalloproteinase

MMPi:

Matrix metalloproteinase inhibitors

ROS:

Reactive oxygen species

TAA:

Thoracic aortic aneurysm

TAD:

Thoracic aortic dissection

TGF-β:

Transforming growth factor-β

vSMC:

Vascular smooth muscle cells

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Authors and Affiliations

  1. Faculty of Medicine, Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, Canada

    N. E. H. Dinesh & D. P. Reinhardt

  2. Department of Anatomy and Cell Biology, McGill University, 3640 University Street, H3A 0C7, Montreal, Quebec, Canada

    D. P. Reinhardt

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Dinesh, N.E.H., Reinhardt, D.P. Inflammation in thoracic aortic aneurysms. Herz 44, 138–146 (2019). https://doi.org/10.1007/s00059-019-4786-7

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