A Novel Mechanism For Atherosclerotic Calcification: Potential Resolution Of The Oxidation Paradox

Keywords

atherosclerosis; azelaic acid; calcification; dicarboxylic acids; lipid peroxides

Abstract

Aim: In this study, we tested the hypothesis that lipid peroxide-derived dicarboxylic acids (DCAs), by virtue of their ability to bind to calcium (Ca), might be involved in atherosclerotic calcification. We determined the ability of azelaic acid (AzA) to promote calcification in human aortic smooth muscle cells (HASMCs), identified AzA in human calcified atherosclerotic lesions, and compared its levels with control and noncalcified atherosclerotic lesions. Results: HASMCs efficiently converted 9-oxononanoic acid (ONA), a lipid peroxide-derived monocarboxylic aldehyde, to AzA. In vitro incubations of AzA micelles with HASMC resulted in the formation of Ca deposits, which contained AzA. Liquid chromatography-mass spectrometry analysis of human control uninvolved artery, noncalcified, and calcified lesions showed significant increase of AzA in calcified lesions compared with noncalcified and control tissues. Calcified mouse atherosclerotic lesions also showed substantial presence of AzA in Ca complexes. Innovation: This study identifies a DCA, AzA, as an integral part of the Ca complex. The study also demonstrates the conversion of a lipid peroxidation product, ONA, as a potential source of AzA, and establishes the presence of AzA in calcified materials isolated from human and mouse lesions. Conclusion: The presence of AzA as a Ca sequestering agent in atherosclerotic lesions (i) might indicate participation of oxidized low-density lipoprotein (Ox-LDL) derived products in calcification, (ii) explain the potential correlation between calcification and overall plaque burden (as Ox-LDL has been suggested to be involved in atherogenesis), (iii) could contribute to plaque stabilization via its anti-inflammatory actions, and (iv) might explain why antioxidants failed to affect atherosclerosis in clinical studies.

Publication Date

8-10-2018

Publication Title

Antioxidants and Redox Signaling

Volume

29

Issue

5

Number of Pages

471-483

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1089/ars.2017.7362

Socpus ID

85049722987 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85049722987

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