Abstract 20809: Mitochondrial Fusion Plays a Crucial Role in the Effect of Renin-Angiotensin Signal Inhibition on Retarding Arterial Senescence and Atherosclerosis
Introduction: Mitochondria are dynamic organelles that undergo fusion and fission. Renin-angiotensin signal (RAS) accelerates arterial senescence and develops arteriosclerosis. This study aims to clarify whether mitochondrial dynamics is involved in the effect of RAS inhibition on arterial senescence and atherosclerosis.
Methods & Results: We used C57BL6, apolipoprotein E knockout (ApoE KO) and double KO mice (DKO) of angiotensin II type Ia receptor KO and ApoE KO. Dynamin-related protein 1 (Drp1), which mediates mitochondrial fission, was activated with phosphorylation at serine 616 and mitochondrial fusion assessed by electron microscopy decreased in the artery of ApoE KO compared to age-matched C57BL6. Mfn1/Mfn2, Opa1 and Fis1, which also modulate mitochondrial dynamics, did not differ between them. The degree of arterial senescence and atherosclerosis are greater in ApoE KO than in C57BL6 assessed by senescence associated beta galactosidase and oil red o staining and immunoblot of p-eNOS/eNOS, PAI-1, p21 and p16. ATP production was lower and reactive oxygen species (ROS) production was higher in ApoE KO. DKO showed lower degrees of arterial senescence, ROS generation and atherosclerosis compared to AopE KO. Expression of arterial p-Drp1 at S616 was lower and the number of fused mitochondria and ATP production were higher in DKO than ApoE KO. These results suggest that mitochondrial fusion may be involved in the effect of RAS-inhibition on arterial senescence and atherosclerosis. We also performed in vitro experiment. Smooth muscle cells with either administration of angiotensin II or Drp1 overexpression had fewer fused mitochondria, lower mitochondrial function, higher ROS level and greater degree of arterial senescence, whereas Drp1 knockdown using siRNA induced mitochondrial fusion and improved mitochondrial function and arterial senescence. Finally, we conducted rescue experiment in vivo. Administration of mdivi1, a pharmacological Drp1 inhibitor, to ApoE KO induced more fused mitochondria, improved mitochondrial function, decreased ROS level and retarded arterial senescence and atherosclerosis.
Conclusion: Mitochondrial fusion plays a crucial role to retard arterial senescence and atherosclerosis by RAS-inhibition.
Author Disclosures: Y. Ikeda: None. M. Iwabayashi: None. Y. Sasaki: None. Y. Akasaki: None. K. Higuchi: None. M. Miyata: None. M. Ohishi: None.
- © 2016 by American Heart Association, Inc.