Pharmacologic blockade and genetic deletion of androgen receptor attenuates aortic aneurysm formation John P. Davis, MD, Morgan Salmon, PhD, Nicolas.

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Pharmacologic blockade and genetic deletion of androgen receptor attenuates aortic aneurysm formation John P. Davis, MD, Morgan Salmon, PhD, Nicolas H. Pope, MD, Guanyi Lu, MD, PhD, Gang Su, MD, Akshaya Meher, PhD, Gorav Ailawadi, MD, Gilbert R. Upchurch, MD Journal of Vascular Surgery Volume 63, Issue 6, Pages 1602-1612.e2 (June 2016) DOI: 10.1016/j.jvs.2015.11.038 Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 1 Scheme of experimental arms. A, Subcutaneous delivery of drugs for wild-type (WT) mice, including aortic perfusion of elastase alone (n = 7), perfusion with heat-inactivated elastase (HIE) alone (n = 9), subcutaneous osmotic pump placement of flutamide (50 mg/kg; n = 9), and subcutaneous placement of ketoconazole tablet (150 mg/kg over 14 days; n = 9). B, Genetic deletion of androgen receptors (ARs) including aortic perfusion of elastase alone (n = 7), perfusion with HIE alone (n = 9), and elastase perfusion of aortas from AR knockout (AR−/−) mice (n = 8). Journal of Vascular Surgery 2016 63, 1602-1612.e2DOI: (10.1016/j.jvs.2015.11.038) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 2 Upregulation of murine androgen receptors (ARs) in aortic aneurysm tissue. A, Messenger RNA (mRNA) expression of ARs of murine aortas perfused with elastase vs saline over a period of 14 days (n = 5 mice per group).∗P < .05. The error bars show the standard error of the mean. B, Immunohistochemistry staining for ARs in murine abdominal aortic aneurysm (AAA) tissue revealing increasing expression of ARs over a period of 14 days (arrows). Photomicrograph bars = 100 μm. C, Confocal microscopy reveals AR staining (purple) concomitantly staining with smooth muscle α-actin (SMαA; red) as indicated by arrows. Macrophage (Mac; green), nuclei (4′,6-diamidino-2-phenylindole; blue). Journal of Vascular Surgery 2016 63, 1602-1612.e2DOI: (10.1016/j.jvs.2015.11.038) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 3 Pharmacologic androgen receptor (AR) blockade and androgen synthesis disruption significantly attenuate experimental aneurysm formation. A, Aortic diameter measured with video micrometry of mice treated with flutamide and ketoconazole revealing significant attenuation of aneurysm development when compared with elastase (P = .013 and P = .0002, respectively). B, Representative immunohistochemistry of aortas treated with elastase alone, heat-inactivated elastase (HIE), and elastase with flutamide and ketoconazole. NS, Not significant; Sm, smooth muscle; VVG, Verhoeff-Van Gieson. Journal of Vascular Surgery 2016 63, 1602-1612.e2DOI: (10.1016/j.jvs.2015.11.038) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 4 Genetic androgen receptor (AR) deletion significantly attenuates experimental aneurysm formation. A, Aortic diameter measured with video micrometry of AR knockout (ARKO−/−) mice reveals significant attenuation of aneurysm development compared with elastase (P < .0001). B, Representative immunohistochemistry of aortas from ARKO−/− mice. The error bars show the standard error of the mean. HIE, Heat-inactivated elastase; NS, not significant; Sm, smooth muscle; VVG, Verhoeff-Van Gieson. Journal of Vascular Surgery 2016 63, 1602-1612.e2DOI: (10.1016/j.jvs.2015.11.038) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 5 Pharmacologic androgen receptor (AR) blockade and genetic AR deletion decrease proinflammatory cytokines. A, Aortic aneurysm tissues from mice treated with flutamide and AR knockout (ARKO−/−) mice reveal significantly decreased expression of the proinflammatory cytokines interferon (IFN)-γ, interleukin (IL)-1α, IL-6, and IL-17. B, Representative immunohistochemistry reveals a trend toward decreased expression of IFN-γ in aneurysm tissues of mice treated with flutamide and aneurysm tissues of AR−/− mice compared with elastase controls. C, Representative immunohistochemistry reveals a trend toward decreased expression of IL-6 in aneurysm tissues of mice treated with flutamide and aneurysm tissues of AR−/− mice compared with elastase controls. The error bars show the standard error of the mean. NS, Not significant. Journal of Vascular Surgery 2016 63, 1602-1612.e2DOI: (10.1016/j.jvs.2015.11.038) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 6 Upregulation of androgen receptors (ARs) in human abdominal aortic aneurysm (AAA) tissue. A, AR levels are increased in AAA tissue from male compared with female patients (n = 10 per group). ∗P < .05 vs female AAA. B, Enzyme-linked immunosorbent assay of human aortic tissue reveals increased levels of ARs in aneurysm tissues compared with control aortic tissues in both men and women (n = 10 samples per group). The error bars show the standard error of the mean. mRNA, Messenger RNA. Journal of Vascular Surgery 2016 63, 1602-1612.e2DOI: (10.1016/j.jvs.2015.11.038) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Supplementary Fig 1 (online only) Schematic shows the experimental arm. A, Intraperitoneal delivery of drugs for wild-type (WT) mice, including aortic perfusion of elastase alone (n = 7), perfusion with heat-inactivated elastase (HIE) alone (n = 9), flutamide (50 mg/kg) (n = 9), and ketoconazole tablet (150 mg/kg over 14 days; n = 9). B, Pharmacologic androgen receptor (AR) blockade and androgen synthesis disruption significantly attenuate experimental aneurysm formation. Aortic diameter measured with video micrometry of mice treated with intraperitoneal flutamide and ketoconazole revealing significant attenuation of aneurysm development compared with elastase (P = .003 and P = .018, respectively). The error bars indicate the standard error of the mean. Journal of Vascular Surgery 2016 63, 1602-1612.e2DOI: (10.1016/j.jvs.2015.11.038) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Supplementary Fig 2 (online only) Immunohistochemistry staining densities of aortic tissues. Macrophages stained significantly less dense in tissues that underwent pharmacologic blockade and genetic deletion of androgen receptors (ARs). No significant differences were detected between immunohistochemistry staining densities between treatment groups with regards to elastin degradation, smooth muscle cell (SMC) staining density, nor T-cell staining density. Macrophages stained significantly less dense in tissues that underwent pharmacologic blockade and genetic deletion of ARs (AR−/−). The error bars show the standard error of the mean. ARKO, Androgen receptor knockout; HIE, heat-inactivated elastase; NS, not significant. Journal of Vascular Surgery 2016 63, 1602-1612.e2DOI: (10.1016/j.jvs.2015.11.038) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Supplementary Fig 3 (online only) Immunohistochemistry staining of androgen receptors (ARs) in human aortic tissues. AR levels are increased in aortic aneurysm tissue compared with normal aorta (arrows). Journal of Vascular Surgery 2016 63, 1602-1612.e2DOI: (10.1016/j.jvs.2015.11.038) Copyright © 2016 Society for Vascular Surgery Terms and Conditions