Expression of the Peroxisome Proliferators–Activated Receptors in Ex Vivo Arterial Tissue of Patients with Abdominal Aortic Aneurysms and Its Association With Wall Remodeling and Inflammatory Gene Expression

Background

The pathogenesis of abdominal aortic aneurysms (AAAs) is multifactorial, characterized by complex pathophysiological processes, including cytokine secretion and protease-mediated degradation of the arterial extracellular matrix (ECM). Peroxisome proliferators–activated receptors (PPARs) are a group of nuclear receptors that regulate the expression of genes for metabolic enzymes and cytokines. However, the molecular mechanisms of PPARs on vascular physiology are not fully evaluated. Our objective was to assess the association between the expression of PPARs in ex vivo aortic tissue and the gene expression of markers of arterial remodeling and inflammation.

Methods

Two aortic tissue samples were obtained from 20 patients (mean age 69 years, standard deviation 5) who underwent open AAA repair. One from the aneurysmal sac and other from the nondiseased adjacent aortic tissue. Four micrometers sections of formalin-fixed and paraffin embedded samples were stained with hematoxylin and eosin, Masson's trichrome and Verhoeff-van Gieson for histopathologic evaluation and arterial wall thickness morphometry. Total RNA was extracted and retrotranscribed to determine PPARs, matrix remodeling proteins, and cytokine gene expression by real-time polymerase chain reaction using specific forward and reverse oligonucleotides and SybrGreen master mix. Statistical analysis was conducted using the nonparametric Mann–Whitney U-test in Prism 8 for Mac (GraphPad, San Diego, CA, USA).

Results

Aneurysm biopsies demonstrated loss of smooth muscle cells, and fragmented and disorganized elastic fibers and changes in ECM composition. The expression of PPARα, PPARδ, and PPARγ was significantly lower in the aneurysmal aorta compared to the nondiseased control tissue from the same patients (59%, 61%, and 42%, respectively, P < 0.01). The expression of the matrix metalloproteinase inhibitor tissue inhibitor of metalloproteinase 4 was significantly reduced in the aneurysmal tissue compared to control (64%), whereas that of the vascular ECM–degrading enzyme cathepsin S was 7-fold higher in the aneurysmal aortic tissue (P < 0.01). Gene expression of monocyte chemoattractant protein-1 and the cytokines tumor necrosis factor α and interleukin-1β was significantly upregulated in the aneurysmal tissue compared to the control nondiseased tissue (20-fold, 83-fold, and 18-fold, respectively, P < 0.001).

Conclusion

These results confirm an inverse correlation between PPARs gene expression and inflammatory cytokine mRNA levels, along with an unfavorable arterial remodeling gene expression. The decrease in the expression of the three PPAR isoforms in the aortic tissue appears to promote abnormal arterial remodeling and the production of proinflammatory cytokines leading to wall thinning and AAA progression.