COBRE Pilot: Role of the X Chromosome Gene, Kdm5c, in Aortopathies

Abstract: Role of the X chromosome gene, Kdm5c, in aortopathies Aortopathies, including thoracic and abdominal aortic aneurysms, are life threatening conditions resulting in high morbidity and mortality from aortic rupture. Aortopathies are sexually dimorphic, occurring at a greater prevalence and severity in males than females. Previous studies demonstrated that sex hormones contributed to sexual dimorphism of experimental aortopathies induced by infusion of angiotensin II (AngII) to mice. More recently, we demonstrated that the sex chromosome complement was an additional biologic sex determinant that influences AngII-induced aortopathies. Namely, an XX sex chromosome complement protected female mice from AngII-induced aortopathies. This finding is clinically significant because Turner’s Syndrome, where females are born with one X chromosome, is associated with a pronounced increase in risk for thoracic aortopathies and aortic rupture. To define mechanisms for our findings, we examined expression of genes on the X chromosome that are known to escape X-inactivation in mice and humans. Kdm5c, chromatin histone lysine demethylase, was expressed at higher level in aortas from XX than XO female mice. Single cell genomics revealed that this gene was expressed at higher levels in smooth muscle cells from ascending aortas of women than men, with reductions in its expression level in aneurysmal aortas of both sexes. In this proposal we will determine the role of Kdm5c gene dosage on the development of AngII-induced aortopathies in mice as a mechanism contributing to sex differences in aortopathies which could potentially identify downstream targets for therapeutic development.