Abstract 432: The Atypical Cadherin Fat1 Suppresses Mitochondrial Function to Control Vascular Smooth Muscle Cell Growth After Vascular Injury
In response to vascular injury, vascular smooth muscle cells (SMCs) undergo phenotypic switching, with enhanced cell cycle entry and migration, and loss of contractile protein expression. Previously, we found that the atypical cadherin Fat1 is upregulated in SMCs after vascular injury. In cultured SMCs, Fat1 is induced by growth factor stimulation, but limits SMC proliferation. Recently, we found that Fat1 species accumulate in SMC mitochondria and interact with critical proteins, including Complex I subunits. The factors governing and significance of mitochondrial activity during SMC response to vascular injury are unclear. We hypothesized that Fat1 controls mitochondrial activity to regulate SMC growth. In cultured SMCs, loss of Fat1 increased mitochondrial oxygen consumption rate (24.8±2.2 vs. 48.1±5.4 pMoles/min, WT vs. Fat1 knockout (KO), p<0.001, n=10), maximal respiratory capacity (35.8±3.4 vs. 55.4±5.4 pMoles/min, WT vs. KO, p<0.01, n=10), oxygen consumed for ATP production (13.1±1 vs. 27.3±3.3 pMoles/min, WT vs. KO, p=0.0005, n=10), and Complex I activity (1.0±0.04 vs.1.3±0.09 RU, WT vs. KO, p<0.034, n=10). Reactive oxygen species (ROS) also increased in Fat1 KO SMCs (1426±313 vs.1848±329 dihydroethidium fluorescence intensity/cell, WT vs. KO, p<0.002, n=3). SMCs lacking Fat1 exhibited enhanced growth (p<0.0001, n=12) and dedifferentiation; adding Rotenone to inhibit Complex I function opposed this growth advantage (p<0.0001, n=6). In a mouse model of vascular injury, SMC Fat1 deletion caused early and exuberant medial hyperplasia, (0.23±0.23 vs.7.16±1.62%, WT n=5 vs. KO n=8, p<0.003, day 3 post-injury) and neointimal expansion (0.18±0.05 vs.0.55±0.1 I/M ratio, WT n=5 vs. KO n=8, p<0.02, day 14 post-injury). We also found higher neointimal cell proliferation (7.7±2 vs. 26±7.1% of pHH3 positive nuclei, WT vs. KO, p=0.041, n=6) and ROS production in Fat1-deleted vessels after injury. In conclusion, we show that the atypical cadherin Fat1 communicates with mitochondrial Complex I to repress energy and ROS production, acting as a molecular “brake” on mitochondrial activity to suppress SMC growth after vascular injury. This novel mechanism could serve as an effective target in the treatment of hyperproliferative vascular diseases.
Author Disclosures: L. Cao: None. D.F. Riascos Bernal: None. P. Chinnasamy: None. C.M. Dunaway: None. M.A. Pujato: None. A. Fiser: None. N.E.S. Sibinga: None.
- © 2015 by American Heart Association, Inc.