Testosterone Metabolite 6β‐Hydroxytestosterone Contributes to Angiotensin II‐Induced Abdominal Aortic Aneurysms in Apoe ^–/– Male Mice

Abstract

Background Sex is a prominent risk factor for abdominal aortic aneurysms (AAAs), and angiotensin II (Ang II) induces AAA formation to a greater degree in male than in female mice. We previously reported that cytochrome P450 1B1 contributes to the development of hypertension, as well as AAAs, in male mice. We also found that a cytochrome P450 1B1‐generated metabolite of testosterone, 6β‐hydroxytestosterone (6β‐OHT), contributes to Ang II‐induced hypertension and associated cardiovascular and renal pathogenesis in male mice. The current study was conducted to determine the contribution of 6β‐OHT to Ang II‐induced AAA development in Apoe –/– male mice. Methods and Results Intact or castrated Apoe –/– /Cyp1b1 +/+ and Apoe –/– /Cyp1b1 –/– male mice were infused with Ang II or its vehicle for 28 days, and administered 6β‐OHT every third day for the duration of the experiment. Abdominal aortas were then evaluated for development of AAAs. We observed a significant increase in the incidence and severity of AAAs in intact Ang II‐infused Apoe –/– /Cyp1b1 +/+ mice, compared with vehicle‐treated mice, which were minimized in castrated Apoe –/– /Cyp1b1 +/+ and intact Apoe –/– /Cyp1b1 –/– mice infused with Ang II. Treatment with 6β‐OHT significantly restored the incidence and severity of AAAs in Ang II‐infused castrated Apoe –/– /Cyp1b1 +/+ and intact Apoe –/– /Cyp1b1 –/– mice. However, administration of testosterone failed to increase AAA incidence and severity in Ang II‐infused intact Apoe –/– /Cyp1b1 –/– mice. Conclusions Our results indicate that the testosterone‐cytochrome P450 1B1‐generated metabolite 6β‐OHT contributes to Ang II‐induced AAA development in Apoe –/– male mice.

ER stress mediates Angiotensin II-augmented innate immunity memory and facilitates distinct susceptibilities of thoracic from abdominal aorta to aneurysm development

“…The aortic arch and thoracic aorta develop higher incidences of atherosclerosis but a relatively lower incidence of Ang II-induced aortic aneurysm ( 33 – 37 ) than the abdominal aorta in the HFD-fed ApoE-KO plus Ang II infusion model ( Figure 1A ). However, the detailed transcriptomic mechanisms underlying the phenotypic differences remained poorly defined ( 5 , 38 – 40 ).…”

The epigenomic landscape of single vascular cells reflects developmental origin and identifies disease risk loci

“…Vascular bed specific expression of Cyp1b1 is particularly notable as it contributes to abdominal aortic aneurysm and suggests a vascular bed specific mechanism of aneurysm (Supplemental Table 11). 68, 69…”

“…Cyp1b1 has a particularly important role in mediating the formation of abdominal aortic aneurysm in mice. 68,69 Our observation that Cyp1b1 has higher expression and greater chromatin accessibility within the endothelium of the descending aorta and that this gene plays particular importance in the development of aneurysm within this vascular bed suggests this gene to have a selective role in mediating vascular bed specific disease risk. This is a particularly interesting observation as exposure to cigarette smoke carries a high risk for developing abdominal aortic aneurysm and cigarette smoke itself is a strong inducer of Cyp1b1, calling into question the potential 'Gene X Environment' interaction in mediating risk of abdominal aortic aneurysm.…”

“…Vascular bed specific expression of Cyp1b1 is particularly notable as it contributes to abdominal aortic aneurysm and suggests a vascular bed specific mechanism of aneurysm (Supplemental Table 11). 68,69 Motif accessibility analysis was performed comparing ascending and descending aortic endothelial cell populations. Top differentially accessible motifs reveal a significant increase in accessibility of multiple ETS factor motifs (E26 Transformation-specific Sequence) in the descending aorta (Figure 4L).…”

6β-Hydroxytestosterone Promotes Angiotensin II-Induced Hypertension via Enhanced Cytosolic Phospholipase A 2 α Activity

“…We used a Pannoramic scanner (3DHISTECH, Budapest, Hungary) available in the UTHSC Core Facility for collagen detection in the heart and kidney sections as described previously. 17 The dihydroethidium-stained sections were visualized using a fluorescence microscope (model IX50, Olympus America) with a dual-wavelength filter, excitation at 375 nm, and emission at 585 nm described previously. 18 The images were viewed and quantified by blinded investigators using ImageJ 1.42 analysis software (NIH: http://imagej.nih.gov/ij).…”