Abstract 16983: Inhibition of Dynamin-Related Protein 1 Accelerates Vascular Calcification in apoE-Deficient Mice through AKT Activation
Background: Mitochondrial dysfunction has been implicated in the pathogenesis of cardiovascular disease. Dynamin-related protein 1 (DRP1) regulates mitochondrial function by driving membrane fission and allowing mitochondria to divide. How DRP1 acts in atherosclerosis, including the development of vascular calcification however remains unknown.
Methods and Results: Aortic smooth muscle mitochondria from apoE-deficient mice (apoE-/-) exhibited a 47% increase in size compared to mitochondria from wild-type mice fed the same atherogenic diet for 18 weeks (N=103-129 mitochondria from 3 mice/group; p<0.05). In agreement with the observed changes in mitochondrial morphology, inhibitory phosphorylation of DRP1 on Ser637 was enriched in apoE-/- mouse aortas. DRP1 immunoreactivity increased around calcified areas of apoE-/- mouse aortic sections. Additionally, DRP1 mRNA was increased 1.8-fold in calcified over non-calcified areas (N=8; p<0.05). To determine the role of DRP1 inhibition on aortic lesion calcification, apoE-/- mice maintained on an atherogenic diet for 13 weeks (a point prior to calcified lesion development) were subsequently given the DRP1 inhibitor, MDIVI-1 (50mg/kg, i.p., once a week) for 5 more weeks. MDIVI-1 administration led to a 65% increase in calcified lesion area without altering lesion size (N=26 mice/group; p<0.05). A single injection of MDIVI-1 resulted in a 3-fold increase in the ratio of phospho-AKT to total pan-AKT along with a strong increase in Runx2 protein in the apoE-/- mouse aorta 6 hours post-injection. MDIVI-1 administration did not alter bone remolding as detected by micro-CT in wild type or apoE-/- mice (N=5 mice/group).
Conclusion: We provide novel roles of the mitochondrial fission protein DRP1 in the vascular calcification process, and demonstrate that inhibition of DRP1 through administration of the DRP1 inhibitor MDIVI-1 in apoE-/- mice accelerates vascular calcification through the AKT/Runx2 pathway.
Author Disclosures: M. Rogers: None. N. Maldonado: None. T. Fiats: None. C. Goettsch: None. J.D. Hutcheson: None. I. Yamada: None. M. Aikawa: Research Grant; Modest; NIH, Kowa company. Research Grant; Significant; >10,000, >10,000. E. Aikawa: Research Grant; Modest; NIH. Research Grant; Significant; >10,000.
- © 2014 by American Heart Association, Inc.