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Suppression of Vascular Macrophage Activation by Nitro-Oleic Acid and its Implication for Abdominal Aortic Aneurysm Therapy

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Abstract

Purpose

Abdominal aortic aneurysm (AAA) is one of the leading causes of death in the developed world and is currently undertreated due to the complicated nature of the disease. Herein, we aimed to address the therapeutic potential of a novel class of pleiotropic mediators, specifically a new drug candidate, nitro-oleic acid (NO2-OA), on AAA, in a well-characterized murine AAA model.

Methods

We generated AAA using a mouse model combining AAV.PCSK9-D377Y induced hypercholesterolemia with angiotensin II given by chronic infusion. Vehicle control (PEG-400), oleic acid (OA), or NO2-OA were subcutaneously delivered to mice using an osmotic minipump. We characterized the effects of NO2-OA on pathophysiological responses and dissected the underlying molecular mechanisms through various in vitro and ex vivo strategies.

Results

Subcutaneous administration of NO2-OA significantly decreased the AAA incidence (8/28 mice) and supra-renal aorta diameters compared to mice infused with either PEG-400 (13/19, p = 0.0117) or OA (16/23, p = 0.0078). In parallel, the infusion of NO2-OA in the AAA model drastically decreased extracellular matrix degradation, inflammatory cytokine levels, and leucocyte/macrophage infiltration in the vasculature. Administration of NO2-OA reduced inflammation, cytokine secretion, and cell migration triggered by various biological stimuli in primary and macrophage cell lines partially through activation of the peroxisome proliferator-activated receptor-gamma (PPARγ). Moreover, the protective effect of NO2-OA relies on the inhibition of macrophage prostaglandin E2 (PGE2)-induced PGE2 receptor 4 (EP4) cAMP signaling, known to participate in the development of AAA.

Conclusion

Administration of NO2-OA protects against AAA formation and multifactorial macrophage activation. With NO2-OA currently undergoing FDA approved phase II clinical trials, these findings may expedite the use of this nitro-fatty acid for AAA therapy.

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Funding

This work was supported by grants to E. Chen (R01-HL068878), J. Zhang (R01-HL138139), L. Villacorta (R01-HL123333), Y. Zhao (Rackham Graduate Student Research Grants), B.A. Freeman (P01-HL103455), and the Mouse Metabolic Phenotyping Center at Michigan (MMPC, NIH U2CDK110768).

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Author notes

  1. Yang Zhao and Ziyi Chang contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA

    Yang Zhao, Ziyi Chang, Guizhen Zhao, Haocheng Lu, Wenying Liang, Huilun Wang, Luis Villacorta, Minerva T. Garcia-Barrio, Tianqing Zhu, Yanhong Guo, Yanbo Fan, Lin Chang, Jifeng Zhang & Y. Eugene Chen

  2. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA

    Yang Zhao & Y. Eugene Chen

  3. Department of Metabolism and Endocrinology, Central South University Second Xiangya Hospital, Changsha, Hunan, China

    Ziyi Chang

  4. Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan, China

    Wenhao Xiong

  5. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Yanbo Fan

  6. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Francisco J. Schopfer & Bruce A. Freeman

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  1. Yang Zhao
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  2. Ziyi Chang
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  3. Guizhen Zhao
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  4. Haocheng Lu
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Contributions

Y. Zhao, Z. Chang, G. Zhao, and J. Zhang performed experiments and analyzed results; Y. Zhao, J. Zhang, and Y.E. Chen wrote the paper; H. Lu, W. Xiong, W. Liang, H. Wang, L. Villacorta, T. Zhu, Y. Guo, Y. Fan, L. Chang, M.T. Garcia-Barrio, F.J. Schopfer, B.A. Freeman, J. Zhang provided technical support and discussed the project; J. Zhang and M.T. Garcia-Barrio did critical editing of the manuscript; J. Zhang and Y.E. Chen led the experimental design.

Corresponding authors

Correspondence to Jifeng Zhang or Y. Eugene Chen.

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Conflicts of Interest/Competing Interests

FJS, BAF, and YEC acknowledge an interest in Complexa, Inc. and FJS and BAF in Creegh Pharmaceuticals, Inc.

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The collection of human samples was approved by the Institutional Review Board (Hum00077616).

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Zhao, Y., Chang, Z., Zhao, G. et al. Suppression of Vascular Macrophage Activation by Nitro-Oleic Acid and its Implication for Abdominal Aortic Aneurysm Therapy. Cardiovasc Drugs Ther 35, 939–951 (2021). https://doi.org/10.1007/s10557-020-07031-8

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