Androgen receptor promotes abdominal aortic aneurysm development via modulating inflammatory interleukin-1α and transforming growth factor-β1 expression.
Sex difference is a risk factor for abdominal aortic aneurysm (AAA) formation yet the reason for male predominance remains unclear. Androgen and the androgen receptor (AR) influence the male sex difference, indicating that AR signaling may affect AAA development. Using angiotensin II–induced AAA in apolipoprotein E null mouse models (82.4% AAA incidence), we found that mice lacking AR failed to develop AAA and aorta had dramatically reduced macrophages infiltration and intact elastic fibers. These findings suggested that AR expression in endothelial cells, macrophages, or smooth muscle cells might play a role in AAA development. Selective knockout of AR in each of these cell types further demonstrated that mice lacking AR in macrophages (20% AAA incidence) or smooth muscle cells (12.5% AAA incidence) but not in endothelial cells (71.4% AAA incidence) had suppressed AAA development. Mechanism dissection showed that AR functioned through modulation of interleukin-1α (IL-1α) and transforming growth factor-β1 signals and by targeting AR with the AR degradation enhancer ASC-J9 led to significant suppression of AAA development. These results demonstrate the underlying mechanism by which AR influences AAA development is through IL-1α and transforming growth factor-β1, and provides a potential new therapy to suppress/prevent AAA by targeting AR with ASC-J9.
George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester
Chiung-Kuei
CK
Huang
Jie
J
Luo
Kuo-Pao
KP
Lai
Ronghao
R
Wang
Haiyan
H
Pang
Eugene
E
Chang
Chen
C
Yan
Janet
J
Sparks
Soo Ok
SO
Lee
Joshua
J
Cho
Chawnshang
C
Chang
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053582:Interleukin-1alpha / Q000096:biosynthesis / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics*
C508584:IL1A protein, human; D053582:Interleukin-1alpha; D011944:Receptors, Androgen; D053773:Transforming Growth Factor beta1; D012313:RNA