Abstract 42: Alternative Autophagy Plays a Role in the Effect of RAS-inhibition on Arterial Senescence and Arteriosclerosis

Abstract

Background: Autophagy is a system to maintain cell homeostasis. Besides the conventional form of autophagy (CA) depending on LC3, the presence of an alternative form of autophagy (AA) depending on Ulk1 and Rab9 has recently been reported. Renin-angiotensin-aldosterone (RAS) signal accelerates arterial senescence and develops arteriosclerosis. Whereas inhibition of RAS signal retards arterial senescence and arteriosclerosis, it remains to be elucidated how autophagy is involved in the effect of RAS-inhibition on arterial senescence and arteriosclerosis. Methods: We used double knockout mice (DKO) of angiotensin II type Ia receptor KO and apolipoprotein E KO (apoE KO). Aortic senility and atherosclerotic lesions were measured using senescence associated beta galactosidase (SA-beta Gal) and Oil Red O staining, respectively. Molecular analysis was also performed. Results: The degree of aortic senescence and atherosclerotic lesions in DKO were significantly lower than those of apoE KO, although there was no significant difference in serum lipids profile between them. Aortic expressions of p21 and PAI-1, the level of reactive oxygen species, mitochondrial function and the amount of damaged mitochondria in DKO were significantly lower than in apoE KO. These results suggest that RAS-inhibition retards arterial senescence and arteriosclerosis possibly through the mitochondrial quality control. Whereas electron microscopic analysis revealed the number of autophagosome containing mitochondria are higher in DKO than in apoE KO, there was no difference in the ration of LC3II/LC3I between them, suggesting that CA is not involved in this model. On the other hand, aortic expressions of the ratio of p-Ulk1 at Ser555/total Ulk1 and Rab9 were significantly higher in DKO than apoE KO, suggesting that AA is induced in DKO. Conclusion: Alternative autophagy, but not conventional autophagy, plays a crucial role in the effect of RAS-inhibition on arterial senescence and arteriosclerosis.