Pharmacologic blockade and genetic deletion of androgen receptor attenuates aortic aneurysm formation

Abstract

Background Testosterone is theorized to play a major role in the pathophysiology of abdominal aortic aneurysms (AAAs) as this disease occurs primarily in males. The role of the androgen receptor (AR) in the formation of AAAs has not been well elucidated and therefore it is hypothesized that androgen blockade will attenuate experimental aortic aneurysm formation. Methods Aortas of 8- to 12-week-old male C57Bl/6 wild type (WT) mice or male androgen receptor knockout (AR−/−) mice were perfused with purified porcine pancreatic elastase (0.35 units/ml) to induce AAA formation. Two groups of WT male mice were treated with flutamide or ketoconazole (both androgen receptor blockers, 50mg/kg and 150mg/kg, respectively) twice daily via intraperitoneal injection. Aortas were harvested on day 14 after video micrometry was used to measure AAA diameter. Cytokine arrays and histologic analysis were performed on aortic tissue. Groups were compared using an ANOVA and a Tukey’s post hoc test. Results Flutamide and ketoconazole treatment attenuated AAA formation in WT mice (84.2±22.8%, p=0.009, and 91.5±18.2%, p=0.037) compared with WT elastase. 121±5.23% (mean±SEM). In addition, AR−/− mice showed attenuation of AAA growth (64.4±22.7% P< 0.0001) compared to WT elastase. Cytokine arrays of aortic tissue revealed decreased levels of pro-inflammatory cytokines interleukin (IL)-α, IL-6, and IL-17 in both flutamide-treated and AR−/− groups when compared to controls. Conclusions Pharmacologic and genetic AR blockade cause attenuation of AAA formation. Therapies for AR blockade utilized in prostate cancer may provide medical treatment to halt progression of AAAs in humans.

Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome

“…In this light, androgen signaling may play a broader role in aortic aneurysm and dissection, but the exact mechanism still needs to be elucidated. Prior experience in experimentally induced aneurysm in rodents has suggested that androgen signaling can exacerbate aortic wall inflammation, but little is known about the precise mechanism (51,(53)(54)(55)(56)(57)(58)(59). It is notable that in our mouse model of vEDS, the androgen-dependent risk seen at puberty was not associated with overt inflammation.…”

Identification of key genes and pathways in abdominal aortic aneurysm by integrated bioinformatics analysis

“…According to the degree of each gene, we identified six hub genes with a degree ≥4: AR , CANX , CD44 , DAXX , STAT1 , and TP53 ( Figure 3b) . Compared with those in the aneurysm gene database (AGD), 15 AR , 16 STAT1 , 17 , 18 and TP53 19 were previously reported to be associated with AAA, whereas CANX , CD44 , and DAXX were novel target genes deserving further investigation.…”

Acute Aortic Dissection in a Postmenopausal Female in the Setting of Parenteral Testosterone, Estradiol, and Progesterone Therapy

“…Whereas Alsiraj et al (12) found that female mice with XY sex chromosomes developed severe angiotensin II-induced abdominal aortic aneurysms, increased inflammatory markers, matrix metalloproteinases and oxidative stress when given testosterone. Davis et al (13) showed that giving C57B1/6 male mice intraperitoneal flutamide or ketoconazole, which block androgen receptors, caused a decrease in pro-inflammatory cytokines. The decrease in pro-inflammatory mediators attenuated the formation of aortic aneurysms in these mice, indicating the importance of these inflammatory markers in aortic aneurysm formation.…”