Abstract 285: Oxidized Low Density Lipoprotein and Angiotensin II Causes Vascular Senescence Via AT1R Signal-mediate Mitochondrial Fission

Abstract

Introduction: Metabolic stress including oxidized low density lipoprotein (ox-LDL) and angiotensin II (AngII) cause mitochondrial dysfunction and vascular senescence. Mitochondria are highly dynamic organelles that constantly change their morphology to fusion or fission. This study aims to clarify how mitochondrial dynamics are involved in the etiology of vascular senescence. Methods: VSMC and HUVEC were stimulated by either ox-LDL or AngII. We also conducted in vivo experiment using C57BL6 (WT), apolipoprotein E (ApoE) deficient and the double knockout of ApoE and AT1R (DKO) mice. Results: Either ox-LDL or AngII induced excessive mitochondrial fission though phosphorylation of Drp1 at Ser616, mitochondrial dysfunction assessed by JC1, reactive oxygen species production measured with Mito-Sox Red and Amplex assay and cellular senescence analyzed by senescence associated beta galactosidase staining and immunoblot of p53 and p21 in cells. Administration of mdivi-1, a specific inhibitor of Drp1, restored imbalance of mitochondrial dynamics and these detrimental alterations. Treatment with angiotensin II type1 receptor (AT1R) inhibitor also inactivated Drp1 and improved imbalance of mitochondrial dynamics, mitochondrial dysfunction and cellular senescence. These results suggest that ox-LDL- or AngII-induced mitochondrial dysfunction and cellular senescence were derived from Drp1-dependent mitochondrial fission. Administration of AT1R inhibitor to HUVEC or SMC with ox-LDL prevented cells against excessive mitochondrial fission, its dysfunction and cellular senescence. The degree of vascular senescence was higher, the number of fused mitochondria and mitochondrial function were lower and mitochondrial oxidative stress were higher in either C57BL6 with AngII infusion or ApoE KO mice than those of control or WT mice, respectively. Treatment with mdivi-1 to these mice reduced mitochondrial fission, oxidative stress and attenuated vascular senescence. The number of fused mitochondria and its function were higher and the degree of vascular senescence were lower in DKO than those in ApoE KO mice. Conclusion: Either ox-LDL or AngIIcauses cellular and vascular senescence through AT1R signal-mediated mitochondrial fission.