Abstract 20731: The Atypical Catherin Fat1 Suppresses Mitochondrial Respiration to Limit Vascular Smooth Muscle Cell Injury Response
Introduction: After arterial injury, vascular smooth muscle cells (SMCs) enter the cell cycle, migrate, and decrease contractile protein expression, consistent with dedifferentiation. Concomitantly, they increase expression of the atypical cadherin Fat1. Although the full-length Fat1 sequence encodes a type I transmembrane protein, we have found that Fat1 fragments accumulate in SMC mitochondria and interact with critical proteins, including multiple components associated with the inner mitochondrial membrane.
Hypothesis: We evaluated the hypothesis that Fat1 controls mitochondrial activity to regulate SMC growth and neointimal formation after vascular injury.
Methods: We studied primary WT and Fat1-deficient (KO) SMCs in culture and in vivo in mice, using assays of growth (phospho-histone H3 staining), mitochondrial function (Seahorse assay), respiratory complex activity, reactive oxygen species production (dihydroethidium fluorescence and nitrotyrosine immunohistochemistry), and vascular injury response (morphometry).
Results: In cultured SMCs, Fat1 loss significantly increased mitochondrial oxygen consumption, maximal respiratory capacity, oxygen consumed for ATP production, and Complex I and II activity. The level of reactive oxygen species (ROS) under stressed conditions also increased significantly. SMCs lacking Fat1 showed higher growth and lower differentiation; genetic or pharmacologic inhibition of Complex I function counteracted this growth advantage. In a mouse model of vascular injury, SMC Fat1 deletion allowed early and exuberant medial hyperplasia (3 days after injury), increased neointimal expansion (14 days after injury), and significantly higher neointimal cell proliferation and ROS production.
Conclusions: The atypical cadherin Fat1 undergoes cleavage, and C-terminal Fat1 species translocate to mitochondria, where they interact with mitochondrial respiratory complexes to limit energy flux, electron transport, and ROS production, effectively acting as a molecular “brake” on mitochondrial activity to suppress SMC growth after vascular injury. This mechanism could provide a new target in the treatment of hyperproliferative vascular diseases.
Author Disclosures: L. Cao: None. D. Riascos-Bernal: None. P. Chinnasamy: None. C. Dunaway: None. M. Pujato: None. A. Fiser: None. N. Sibinga: None.
- © 2016 by American Heart Association, Inc.