Kallistatin limits abdominal aortic aneurysm by attenuating generation of reactive oxygen species and apoptosis

Krishna, Smriti Murali, Li, Jiaze, Wang, Yutang, Moran, Corey S., Trollope, Alexandra, Mohamed Omer, Safraz, Huynh, Pacific, Jose, Roby, Biros, Erik, Ma, Jianxing, and Golledge, Jonathan (2021) Kallistatin limits abdominal aortic aneurysm by attenuating generation of reactive oxygen species and apoptosis. Scientific Reports, 11. 17451.

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Abstract

Aims: Inflammation, vascular smooth muscle cell apoptosis and oxidative stress are believed to play important roles in abdominal aortic aneurysm (AAA) pathogenesis. Human kallistatin (KAL; gene SERPINA4) is a serine proteinase inhibitor previously shown to inhibit inflammation, apoptosis and oxidative stress.The aim of this study was to investigate the role of KAL in AAA through studies in experimental mouse models and patients.

Methods and results: Serum KAL concentration was negatively associated with the diagnosis and growth of human AAA. Transgenic overexpression of the human KAL gene (KS-Tg) or administration of recombinant human KAL (rhKAL) inhibited AAA in the calcium phosphate (CaPO4) and subcutaneous angiotensin II (AngII) infusion mouse models, respectively. Upregulation of KAL in both models resulted in reduction in the severity of aortic elastin degradation, reduced markers of oxidative stress and less vascular smooth muscle apoptosis within the aorta. Administration of rhKAL to vascular smooth muscle cells incubated in the presence of AngII or in human AAA thrombus-conditioned media reduced apoptosis and downregulated markers of oxidative stress. These effects of KAL were associated with upregulation of Sirtuin 1 activity within the aortas of both KS-Tg mice and rodents receiving rhKAL.

Conclusions: These results suggest KAL-Sirtuin 1 signalling limits aortic wall remodelling and aneurysm development through reductions in oxidative stress and vascular smooth muscle cell apoptosis. Upregulating KAL may be a novel therapeutic strategy for AAA.

Item ID: 69251
Item Type: Article (Research - C1)
ISSN: 2045-2322
Copyright Information: © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Funders: National Health and Medical Research Council (NHMRC), Queensland Government (QG), Townsville Hospital Private Practice Trust Fund (THPPTF), Research Infrastructure Block Grant (RIBG), James Cook University (JCU)
Projects and Grants: NHMRC grant 1079369, NHMRC grant 1079193, NHMRC grant 1098717, NHMRC Practitioner Fellowship grant 1117061, QG Senior Clinical Research Fellowship, JCU Medicine Incentive Grant
Date Deposited: 01 Sep 2021 04:11
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3201 Cardiovascular medicine and haematology > 320199 Cardiovascular medicine and haematology not elsewhere classified @ 100%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200101 Diagnosis of human diseases and conditions @ 50%
20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 50%
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