Lysyl Oxidase Inhibition Ablates Sexual Dimorphism of Abdominal Aortic Aneurysm Formation in Mice
Authors: Michihiro Okuyama, Weihua Jiang, Aida Javidan, Jeff Zheying Chen, Deborah A. Howatt, Lihua Yang, Mika Hamaguchi, Takumi Yasugi, Jun Aono, Roberto Irenardo Vazquez-Padron, Venkateswaran Subramanian
Journal: Circulation (2020)

angiotensin II ◼ aortic aneurysm, abdominal ◼ protein-lysine 6-oxidase ◼ sex characteristics Editorial, see p 1901 A bdominal aortic aneurysm (AAA) formation involves a complex process of aortic medial destruction through degradation of extracellular matrix proteins, elastin, and collagen.AAA exhibits sexual dimorphism because male sex is a major risk factor of AAA in both mice and humans. 1 In mice, testosterone has been implicated as a major contributor to sexual dimorphism of angiotensin II (AngII)-induced AAAs. 2 However, the mechanism by which testosterone drives sexual dimorphism of AAA is unknown.During aortic development, lysyl oxidase (LOX) covalently cross-links elastin and collagen to create an insoluble extracellular matrix resistant to proteolytic degradation. 3We hypothesized that testosterone-mediated suppression of LOX activity is a critical contributor to increased susceptibility of male to AAA formation.Ethics and institutional review board approvals were provided by University of Kentucky (Protocol-2011-0907) and the Ehime University (Protocol-1603002), and informed consent was received from all participants.To test this hypothesis, we first evaluated LOX protein in human male and female, nonaneurysmal and aneurysmal, abdominal aortic sections.LOX protein was significantly more abundant in the aortic media in female nonaneurysmal and aneurysmal aortic sections than in male nonaneurysmal and aneurysmal aortic sections (Figure A).Consistent with observations in humans, abdominal aortas from female C57BL/6J mice showed significantly more LOX protein in the aortic media than from male mice (Figure B).To discern whether this sexual dimorphism was functionally relevant, we examined LOX activity by measuring breakdown of fluorescent-labeled LOX substrate in aortic tissues from male and female mice infused with either saline or AngII (1000 ng•kg -1 •min -1 ) for 7 days.Consistent with LOX protein abundance, LOX activity in female aortic tissue was ≈2.5-fold significantly higher than in male aortic tissue, and AngII infusion had no influence on LOX activity in either sex (Figure C).To explore whether sex hormones regulate aortic LOX activity, 8-week-old male and female mice were subjected to either castration (orchiectomy or ovariectomy) or sham operation.Four weeks after surgery, abdominal aortic LOX activity was measured.Orchiectomy of male mice not only significantly increased LOX activity, in comparison with sham controls, but to a level present in female mice.Ovariectomy had no influence on LOX activity in female mice in comparison with sham controls (Figure D).Furthermore, testosterone replacement by dihydrotestosterone pellet (16 µg/d subcutaneously) administration for 2 weeks significantly suppressed LOX activity in orchiectomized mice similar to sham controls (Figure E).These results suggest that androgens, not estrogens, regulate and suppress aortic LOX activity in mice.