Abstract P243: Vascular Drp1 Mediates Angiotensin II-Induced Cardiovascular Hypertrophy via Global as Well as Selective de novo Protein Synthesis.

Mitochondrial fission has been implicated in various cardiovascular and metabolic diseases but the role of the mitochondrial fission inducer Drp1 in regulating hypertension and cardiovascular remodeling remains unclear. To study the involvement of Drp1 in cardiovascular hypertrophy, rat aortic vascular smooth muscle cells (VSMCs) are infected with dominant negative (dn) Drp1 adenovirus and stimulated with 100 nM angiotensin II (AngII). In vivo, tamoxiphen-inducible SMMHC-Cre+/- Drp1 floxed mice and control mice are infused with AngII (1000ng/kg/min) for 2 weeks. In VSMCs, AngII-induced mitochondrial fission was attenuated with AT1 blocker RNH6270 (ARB) as well as with dnDrp1 (100 moi). ARB and dnDrp1 treatment also inhibited AngII-enhanced global as well as specific de novo protein synthesis evaluated by SunSet assay. To identify potential mediators downstream of Drp1-mitochondrial fission contributing to VSMC hypertrophy, shotgun proteomic analysis was performed on proteins extracted from AngII or vehicle treated VSMC with dnDrp1 or control adenovirus infection. 22 exclusively regulated proteins induced by AngII and attenuated by dnDrp1 were identified including previously known AngII targets, HMGB1 and PAIRB. In addition, ARB and dnDrp1 inhibited AngII-induced enhancement of mitochondrial ox-phosphorylation and oxidative stress (assessed with mito-timer adenovirus). In vivo, VSMC specific DRP1 silencing suppressed AngII-induced cardiac hypertrophy assessed with heart weight/body weight ratio Mean±SEM: 6.33±0.14 vs 5.25±0.07 (p<0.001) as well as with echocardiogram: LVPWd 1.46±0.02 vs 0.81±0.03 (p<0.001). However, both control and the Drp1 silenced mice developed hypertension when infused with AngII as assessed by DSI radio-telemetry system. In conclusion, these data suggest that Drp1 mediates AngII-induced global as well as specific de novo protein synthesis thereby contributing to cardiovascular hypertrophic remodeling.