Impaired function of aorta and perivascular adipose tissue in IL-18-deficient mice.

Interleukin-18 (IL-18) is ubiquitously produced by both hematopoietic and non-hematopoietic cells, but the central biological role of IL-18 in non-hematopoietic cells has not been sufficiently elucidated. In the present study, we examined the thoracic aorta, including perivascular adipose tissue (PVAT) of the IL-18 knockout (KO) mice in terms of functional and histological aspects.　IL-18KO mice exhibited significantly higher blood pressure compared with wild-type (WT) mice. Echocardiographic examination showed a thickened vascular wall and narrowed vascular diameter of the abdominal aorta. Examination by the Magnus test demonstrated dysfunction of endothelial cells (EC) in the IL-18KO thoracic aorta and impairment of the anti-contractile function of IL-18KO PVAT. Histological examination showed no inflammatory lesions in the aorta, but indicated progressive fibrosis in the vessel, conversion of PVAT from brown adipose tissue-like features to white adipose tissue-like features, and heterogeneous localizations of claudin 5 in the PVAT of IL-18KO mice. Electron microscopic observation revealed several deformed mitochondria in the EC and PVAT, and many vacuoles in the EC of the IL-18KO aorta. ATP productivity and activity of complex IV were decreased in the mitochondria of IL-18KO aorta, and production of reactive oxygen species was augmented. Western blot analysis revealed that a decreased expression of MnSOD, while that of UCP1 and LAMP 1/2 was increased in mitochondria of IL-18KO PVAT. Moreover, cathepsin D activity was decreased in IL-18KO PVAT. Thus, the IL-18KO thoracic aorta had defects in physiological functions related to histological　alterations, which might have been associated with mitochondrial dysfunction in IL-18KO mice.