Cathepsins: a new culprit behind abdominal aortic aneurysm

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Abstract

Abdominal aortic aneurysm (AAA) is a fatal disease defined as an abdominal aortic diameter of 3.0 cm or more, where the abdominal aorta exceeds the normal diameter by more than 50%. Histopathological changes of AAA mainly include extracellular matrix (ECM) remodeling at the abdominal aorta wall, but there is lack of specific drugs to treat AAA. Recent studies have reported that lysosomal cathepsins could induce vascular remodeling and AAA formation by regulating vascular inflammation, medial smooth muscle cell apoptosis, neovascularization, and protease expression. Thus, cathepsins are expected to become a new therapeutic target for AAA treatment.

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Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice.

A Daugherty, M W Manning, L Cassis (2000)

Increased plasma concentrations of angiotension II (Ang II) have been implicated in atherogenesis. To examine this relationship directly, we infused Ang II or vehicle for 1 month via osmotic minipumps into mature apoE(-/-) mice. These doses of Ang II did not alter arterial blood pressure, body weight, serum cholesterol concentrations, or distribution of lipoprotein cholesterol. However, Ang II infusions promoted an increased severity of aortic atherosclerotic lesions. These Ang II-induced lesions were predominantly lipid-laden macrophages and lymphocytes; moreover, Ang II promoted a marked increase in the number of macrophages present in the adventitial tissue underlying lesions. Unexpectedly, pronounced abdominal aortic aneurysms were present in apoE(-/-) mice infused with Ang II. Sequential sectioning of aneurysmal abdominal aorta revealed two major characteristics: an intact artery that is surrounded by a large remodeled adventitia, and a medial break with pronounced dilation and more modestly remodeled adventitial tissue. Although no atherosclerotic lesions were visible at the medial break point, the presence of hyperlipidemia was required because infusions of Ang II into apoE(+/+) mice failed to generate aneurysms. These results demonstrate that increased plasma concentrations of Ang II have profound and rapid effects on vascular pathology when combined with hyperlipidemia, in the absence of hemodynamic influences.

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Management of abdominal aortic aneurysms clinical practice guidelines of the European society for vascular surgery.

F Moll, J T Powell, G Fraedrich … (2011)

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Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells.

G Shi, G S Sukhova, Michael H Chapman … (1998)

Formation of the atherosclerotic intima must involve altered metabolism of the elastin-rich arterial extracellular matrix. Proteases potentially involved in these processes remain unclear. This study examined the expression of the potent elastases cathepsins S and K in human atheroma. Normal arteries contained little or no cathepsin K or S. In contrast, macrophages in atheroma contained abundant immunoreactive cathepsins K and S. Intimal smooth muscle cells (SMC), especially cells appearing to traverse the internal elastic laminae, also contained these enzymes. Extracts of atheromatous tissues had approximately twofold greater elastase-specific activity than extracts of uninvolved arteries, mostly due to cysteine proteases. Cultured human SMC displayed no immunoreactive cathepsins K and S and exhibited little or no elastolytic activity when incubated with insoluble elastin. SMC stimulated with the atheroma-associated cytokines IL-1beta or IFN-gamma secreted active cathepsin S and degraded substantial insoluble elastin (15-20 microg/10(6) cells/24 h). A selective inhibitor of cathepsin S blocked > 80% of this elastolytic activity. The presence of cathepsins K and S at sites of vascular matrix remodeling and the ability of SMC and macrophages to use these enzymes to degrade elastin supports a role for elastolytic cathepsins in vessel wall remodeling and identifies novel therapeutic targets in regulating plaque stability.

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Author and article information

Contributors

Yi Wang: 236426092@qq.com

Chaoshu Tang: tangchaoshu@263.net.cn

Yanwen Qin: qinyanwen@vip.126.com

Journal

Journal ID (nlm-ta): Regen Med Res

Journal ID (iso-abbrev): Regen Med Res

Title: Regenerative Medicine Research

Publisher: BioMed Central (London )

ISSN (Electronic): 2050-490X

Publication date (Electronic): 1 November 2013

Publication date Collection: December 2013

Volume: 1

Issue: 1

Electronic Location Identifier: 5

Affiliations

The Key Laboratory of Remodeling-related Cardiovascular Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029 China

Article

Publisher ID: 16

DOI: 10.1186/2050-490X-1-5

PMC ID: 4431531

PubMed ID: 25984324

SO-VID: ee38e2e4-75be-4b1f-b65d-76811a3df24b

License:

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.