TROVE2 strengthens the anti-inflammatory effect via macrophage polarization by estrogen induction in abdominal aortic aneurysm

Rationale: Blood eosinophil (EOS) count and EOS cationic protein (ECP) associate with human cardiovascular diseases (CVD). Yet, whether EOS play a role in CVD remains untested. The current study detected EOS accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting EOS participation in this aortic disease. Objective: To test whether and how EOS affect AAA growth. Methods and Results: Population-based randomized clinically controlled screening trials revealed higher blood EOS count in 579 male AAA patients than in 5,063 non-AAA control (0.236{plus minus}0.182 vs 0.211{plus minus}0.154, 109/L, P<0.001). Univariate (OR=1.381, P<0.001) and multivariate (OR=1.237, P=0.031) logistic regression analyses indicated that increased blood EOS count in AAA patients served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected EOS accumulation and EOS cationic protein expression in human and murine AAA lesions. Results showed that EOS deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell (SMC) loss using angiotensin-II perfusion-induced AAA in Apoe -/- and EOS-deficient Apoe -/- ;∆dblGATA mice. EOS deficiency increased lesion chemokine expression, muted lesion expression of IL4 and EOS-associated-ribonuclease-1 (mEar1, human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, EOS-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11b+Ly6Chi monocytes, and increased CD11b + Ly6C lo monocytes. mEar1 treatment or adoptive transfer of EOS from WT and Il13 -/- mice, but not EOS from Il4 -/- mice, blocked AAA growth in Apoe -/- ∆dblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for EOS IL4 and mEar1 in blocking NF-κB activation in macrophages, SMCs, and endothelial cells. Conclusions: EOS play a protective role in AAA by releasing IL4 and cationic proteins such as mEar1 to regulate macrophage and monocyte polarization and to block NF-κB activation in aortic inflammatory and vascular cells.

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Modulating Neuro-Immune-Induced Macrophage Polarization With Topiramate Attenuates Experimental Abdominal Aortic Aneurysm

Frontiers in Pharmacology ◽

10.3389/fphar.2020.565461 ◽

2020 ◽

Vol 11 ◽

Author(s):

Xing Chen ◽

Yang Li ◽

Jie Xiao ◽

Hua Zhang ◽

Chuanlei Yang ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Macrophage Polarization ◽

Abdominal Aortic

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Anti-Inflammatory Drug Methotrexate Suppresses Experimental Abdominal Aortic Aneurysm in Mice

Journal of Surgical Research ◽

10.1016/j.jss.2012.10.350 ◽

2013 ◽

Vol 179 (2) ◽

pp. 201

Author(s):

B. Xu ◽

H. Xuan ◽

X. Hu ◽

H. Tanaka ◽

W. Wang ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Inflammatory Drug ◽

Abdominal Aortic ◽

Anti Inflammatory

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IL-1β (Interleukin-1β) and TNF-α (Tumor Necrosis Factor-α) Impact Abdominal Aortic Aneurysm Formation by Differential Effects on Macrophage Polarization

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.117.310333 ◽

2018 ◽

Vol 38 (2) ◽

pp. 457-463 ◽

Cited By ~ 18

Author(s):

Rishi Batra ◽

Melissa K. Suh ◽

Jeffrey S. Carson ◽

Matthew A. Dale ◽

Trevor M. Meisinger ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Tumor Necrosis Factor ◽

Aortic Aneurysm ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Macrophage Polarization ◽

Abdominal Aortic ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

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Elastin-Derived Peptides Promote Abdominal Aortic Aneurysm Formation by Modulating M1/M2 Macrophage Polarization

The Journal of Immunology ◽

10.4049/jimmunol.1502454 ◽

2016 ◽

Vol 196 (11) ◽

pp. 4536-4543 ◽

Cited By ~ 46

Author(s):

Matthew A. Dale ◽

Wanfen Xiong ◽

Jeffrey S. Carson ◽

Melissa K. Suh ◽

Andrew D. Karpisek ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Macrophage Polarization ◽

M2 Macrophage ◽

Aneurysm Formation ◽

Abdominal Aortic ◽

M2 Macrophage Polarization

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Circular RNA Cdyl promotes abdominal aortic aneurysm formation by inducing M1 macrophage polarization and M1-type inflammation

Molecular Therapy ◽

10.1016/j.ymthe.2021.09.017 ◽

2021 ◽

Author(s):

Haoyu Song ◽

Yang Yang ◽

Yili Sun ◽

Guoquan Wei ◽

Hao Zheng ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Macrophage Polarization ◽

Circular Rna ◽

Aneurysm Formation ◽

Abdominal Aortic ◽

M1 Macrophage ◽

M1 Type

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Intravenous ketorolac is associated with reduced mortality and morbidity after open abdominal aortic aneurysm repair

Vascular ◽

10.1177/1708538120914454 ◽

2020 ◽

pp. 170853812091445

Author(s):

Besma Nejim ◽

M Libby Weaver ◽

Satinderjit Locham ◽

Omar Al-Nouri ◽

Isaac N Naazie ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Abdominal Aortic Aneurysm Repair ◽

Exact Matching ◽

Abdominal Aortic ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Aneurysm Repair ◽

Aortic Aneurysm Repair ◽

Intravenous Ketorolac

Objectives The role of non-steroidal anti-inflammatory drugs in aortic aneurysm disease has been debated. Animal studies demonstrated that intrathecal ketorolac reduces the inflammatory response associated with aortic clamping. However, no human-subject study evaluated this association. Therefore, we sought to explore the effects of ketorolac use in open abdominal aortic aneurysm repair. Methods The Premier Healthcare Database (June 2009–March 2015) was inquired to capture patients who underwent open abdominal aortic aneurysm repair for non-ruptured abdominal aortic aneurysm, identified via International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. Intravenous ketorolac was coded as any or none. Outcomes were in-hospital mortality, cardiac, respiratory, renal, neurological, and hemorrhagic complications. Multivariable logistic regression coarsened exact matching followed by conditional fixed-effect regression modeling were performed. Results A total of 6394 patients were identified (ketorolac: 806; 12.6%). Patients who received ketorolac were younger and less likely to have hypertension (76.1% vs. 79.3%), diabetes mellitus (12.5% vs. 17.4%), or chronic kidney disease (8.3% vs. 21.4%; all p values ≤ .033). There was no significant difference in medication use including oral non-steroidal anti-inflammatory drugs and malignant or musculoskeletal diseases. Mortality, respiratory, and renal complications were less prevalent with ketorolac (2.5% vs. 4.9%, 25.2% vs. 34.6%, 10.0% vs. 21.1%; p ≤ .002). Ketorolac was associated with lower adjusted odds for those events: 0.58 (0.36–0.93), 0.53 (0.42–0.68), and 0.72 (0.60–0.86), respectively (all p values ≤ .025). There was no association with neurological, cardiac, or hemorrhagic complications. The findings were replicated by coarsened exact matching analysis. Conclusion This study demonstrated 40% mortality reduction with intravenous ketorolac following open abdominal aortic aneurysm repair. The survival benefit could be due to its anti-inflammatory and opioid-sparing properties. This is evident by its protective effect against respiratory outcomes. The lack of association with the classical non-steroidal anti-inflammatory drugs-related cardiac and hemorrhagic complication could be attributable to the short-term use of ketorolac compared with non-steroidal anti-inflammatory drugs chronic use.

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