Abstract 184: Sirt3 is a Critical Mediator of Diet-induced Vasomotor Dysfunction
Increases in mitochondrial reactive oxygen species (ROS) can contribute to endothelial dysfunction in conduit arteries by reducing nitric oxide bioavailability. SIRT3 is a protein deacetylase localized to mitochondria and regulates activity of numerous electron transport chain enzymes, and can be inactivated by increases in mitochondrial ROS. Whether reductions in SIRT3 are an independent contributor to endothelial dysfunction, however, are unknown. Therefore, we hypothesized that SIRT3 null mice (SIRT3-/-) will have impaired relaxation to acetylcholine (MRAch) compared to wild-type littermates (SIRT3+/+), and that this difference will be exacerbated by Western diet feeding for 3 months (TD88137, 42% of kcal from fat, 0.2% cholesterol). Endothelial function was measured using isolated organ bath chambers, and endothelium-dependent (MRAch) and endothelium-independent (sodium nitroprusside, MRSNP) relaxation were measured. In contrast to our hypothesis, MRACH was virtually identical between SIRT3+/+ and SIRT3-/- fed a standard chow diet (MRACH= 68±2% and 69±3%; respectively), and MRSNP also remained unchanged between the two genotypes. In groups fed a Western diet, however, endothelium-dependent relaxation was significantly impaired in SIRT3-/- mice compared to SIRT3+/+ littermates (MRACH = 49±4% and 58±3%, respectively; p<0.05). MRSNP was not altered by either Western diet feeding or SIRT3 deficiency. Interestingly, impairments in MRAch in SIRT3-/- mice fed a Western diet were not rescued with acute incubation of apocynin (an NAD(P)H oxidase inhibitor) or mito-tempol (a mitochondria-targeted antioxidant), suggesting that chronic antioxidant and/or acetyltransferase inhibition may be required to improve vasomotor function in this model. Collectively, our data suggest that SIRT3 plays a major role in regulating endothelial function with dietary stress, and may be a useful therapeutic target to reduce cardiovascular risk.
- © 2013 by American Heart Association, Inc.