Vascular smooth muscle cell peroxisome proliferator-activated receptor-γ deletion promotes abdominal aortic aneurysms Milton Hamblin, PhD, Lin Chang,

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Vascular smooth muscle cell peroxisome proliferator-activated receptor-γ deletion promotes abdominal aortic aneurysms Milton Hamblin, PhD, Lin Chang, MD, PhD, Hengmin Zhang, MD, Kun Yang, MD, Jifeng Zhang, MS, Y. Eugene Chen, MD, PhD Journal of Vascular Surgery Volume 52, Issue 4, Pages 984-993 (October 2010) DOI: 10.1016/j.jvs.2010.05.089 Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 1 The maximum external aortic diameter is greater in vascular smooth muscle cell-selective peroxisome proliferator-activated receptor-γ knockout mice (SMPG KO) compared with wild-type mice. A, Representative photographs of aortas from SMPG KO and wild-type mice treated with CaCl2 or NaCl (control). SMPG KO mice exhibited a greater increase in the external diameter of the infrarenal aorta than did wild-type mice 6 weeks after periaortic injury with CaCl2 (P = .000119). There is no difference in the size of the diameter between groups administered NaCl (unpublished data). B, The results are shown as mean ± standard error of the mean (n = 7 mice for SMPG KO group, n = 8 mice for wild-type group). P < .01 vs wild-type group (two-way analysis of variance). Journal of Vascular Surgery 2010 52, 984-993DOI: (10.1016/j.jvs.2010.05.089) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 2 Vascular smooth muscle cell-selective peroxisome proliferator-activated receptor-γ knockout (SMPG KO) mice have increased destruction of medial layer elastic architecture. Representative elastic van Gieson staining of aortic sections after periaortic application of (top row) NaCl or (bottom row) CaCl2. At 6 weeks after the periaortic application of 0.25M CaCl2, medial layer elastic lamellae are degraded in (A, B) SMPG KO and (C, D) wild-type mice. However, elastin degradation is more pronounced in (A, B) SMPG KO compared with (C, D) wild-type mice 6 weeks after 0.25M CaCl2 periaortic application. SMPG KO mice administered CaCl2 demonstrate an increasing number of elastic strand breaks vs wild-type mice. The arrows indicate disruption of elastic network in the medial layer. At 6 weeks after periaortic application of 0.25M NaCl, medial layer elastic lamellae are largely intact in (E, F) SMPG KO and (G, H) wild-type mice. The Insert Table in Fig 2 is based on elastin degradation scoring (see details in Methods) of sections from periaortically-injured (CaCl2) SMPG KO (n = 42 sections from 7 mice) and wild-type (n = 48 sections from 8 mice) animals. Each section was assigned a grade of I to IV, because increasing grades indicate greater severity of elastin destruction. Histologic scoring shows that SMPG KO mice have significantly increased medial layer elastic destruction compared with wild-type mice. P < .01 vs wild-type group (χ2). Journal of Vascular Surgery 2010 52, 984-993DOI: (10.1016/j.jvs.2010.05.089) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 3 Vascular smooth muscle cell (VSMC) peroxisome proliferator-activated receptor (PPAR)-γ reduces cathepsin S expression. Real-time polymerase chain reaction analysis for cathepsins S, K, and L1 was performed using cultured rat aortic smooth muscle cells (RASMCs). Transfected adenoviruses were used to overexpress PPARγ (Ad-PPARγ) in VSMC. PPARγ overexpression in RASMCs decreased the relative messenger RNA (mRNA) expression levels of cathepsin S by half the amount (P = .022). However, PPARγ had no effect on the relative mRNA levels of either cathepsin K or cathepsin L1. Thus, the data demonstrate that VSMC PPARγ effects on mRNA levels are selective for cathepsin S. An adenovirus carrying green fluorescent protein (Ad-GFP) was used as the control. Results were normalized by arbitrarily setting Ad-GFP group levels to 1.0 (n = 4 for each group and experiments were performed 3 separate times). Data are shown as mean ± standard error of the mean. P = .022 vs Ad-GFP group (two-way analysis of variance). Journal of Vascular Surgery 2010 52, 984-993DOI: (10.1016/j.jvs.2010.05.089) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 4 Vascular smooth muscle (VSMC) peroxisome proliferator-activated receptor (PPAR)-γ deletion increases activated cathepsin S in mouse aortas. VSMC-selective PPARγ knockout (SMPG KO) mice show evidence of increased activated cathepsin S compared with wild-type mice 1 week after periaortic injury with CaCl2. Upper panel, As expected, PPARγ is absent in the aorta of SMPG KO mice. Middle panel, Activated cathepsin S is increased in periaortic injury-induced (CaCl2) SMPG KO mice vs wild-type mice. Furthermore, SMPG KO mice periaortically administered NaCl also display an elevation in activated cathepsin S compared with wild-type mice. A total of n = 3 for each pooled sample. Bottom panel, The β-tubulin served as a protein loading control. Journal of Vascular Surgery 2010 52, 984-993DOI: (10.1016/j.jvs.2010.05.089) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 5 Peroxisome proliferator-activated receptor (PPAR)-γ decreases activated cathepsin S in vascular smooth muscle cells (VSMCs). Analysis for cathepsin S was performed using cultured rat aortic SMCs (RASMCs). A, Overexpression of adenoviral-carried PPARγ (Ad-PPARγ) results in reduction of the active form of cathepsin S. On the other hand, knockdown of PPARγ via adenoviral-carried PPARγ RNA interference (Ad-PPARγ RNAi) in VSMCs leads to increased levels of cathepsin S in its active form. An adenovirus carrying green fluorescent protein (Ad-GFP) was used as the adenovirus control. B, A cathepsin S activity assay was performed using RASMCs transfected with adenoviruses either overexpressing or knocking down PPARγ. PPARγ overexpressed in VSMCs reduces cathepsin S activity (P = .013), whereas PPARγ knockdown significantly increases cathepsin S activity (P = .018). Results of activity assay were normalized by arbitrarily setting the cathepsin S activity of the Ad-GFP group to 1.0 (n = 4 for each group; experiments were performed 3 separate times). Data are shown as mean ± standard error of the mean. P < .05 vs Ad-GFP group (two-way analysis of variance). Journal of Vascular Surgery 2010 52, 984-993DOI: (10.1016/j.jvs.2010.05.089) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 6 Peroxisome proliferator-activated receptor (PPAR)-γ binds specifically to a putative PPAR response element in the cathepsin S promoter region. Mouse aortic smooth muscle cells were transfected with a pcDNA3.1 vector with or without Flag-PPARγ. A chromatin immunoprecipitation (ChIP) assay detected PPARγ bound to a PPAR response element (PPRE) upstream of the cathepsin S gene sequence. The ChIP assay was performed by immunoprecipitating cathepsin S chromatin and input. Polymerase chain reaction was used to amplify the desired DNA sequence containing the targeted PPRE (−141 to −159 bp upstream). This experiment was conducted three separate times. M, Marker; NC, negative control. Journal of Vascular Surgery 2010 52, 984-993DOI: (10.1016/j.jvs.2010.05.089) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 7 A, B, Representative immunohistochemical sections of F4/80 and tumor necrosis factor (TNF)-α expression 6 weeks after periaortic CaCl2 application demonstrates the medial layer of vascular smooth muscle cell (VSMC)-selective peroxisome proliferator-activated receptor (PPAR)γ knockout (SMPG KO) mice contains increased expression of F4/80 compared with control mice (P = .021). C, D, In addition, the medial layer area expressing TNF-α is also greater in SMPG KO mice vs wild-type mice (P = .015) after 6 weeks (C, D). The scale bars = 50 μm. Results shown as mean ± standard error of the mean (4 to 6 sections per animal, n = 3 mice for each group). P < .05 vs wild-type group (two-way analysis of variance). Journal of Vascular Surgery 2010 52, 984-993DOI: (10.1016/j.jvs.2010.05.089) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Appendix Fig I Journal of Vascular Surgery 2010 52, 984-993DOI: (10.1016/j.jvs.2010.05.089) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Appendix Fig II Journal of Vascular Surgery 2010 52, 984-993DOI: (10.1016/j.jvs.2010.05.089) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Appendix Fig III Journal of Vascular Surgery 2010 52, 984-993DOI: (10.1016/j.jvs.2010.05.089) Copyright © 2010 Society for Vascular Surgery Terms and Conditions