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Effects of SIRT3 deficiency on vasomotor function and atherosclerotic plaque composition in mice

Excess mitochondrial reactive oxygen species can drive endothelial dysfunction and vascular calcification in atherosclerosis. Recently, SIRT3 has been linked to the activity of the ROS‐degrading enzyme MnSOD through regulation of protein acetylation levels. It remains unclear, however, whether SIRT3 protects against endothelial dysfunction and osteogenic signaling in hypercholesterolemia. We hypothesized, that reduction of SIRT3 will impair endothelial function, decrease mitochondrial antioxidant capacity, and increase osteogenic signaling in hypercholesterolemic mice. We used Ldlr−/−/ApoB100/100 (LA) mice that were either wild‐type (LA‐SIRT3+/+) or null for SIRT3 (LA‐SIRT3−/−). After 12 months of western diet feeding, we assessed endothelial function in aorta using isolated organ chamber baths and measured changes in gene expression using qRT‐PCR. As expected, SIRT3 gene expression was significantly reduced in LA‐SIRT3+/− mice compared to LA‐SIRT3+/+ mice, and undetectable in LA‐SIRT3−/−. Surprisingly, endothelial‐dependent relaxation to acetylcholine (MRAch) was unchanged between LA‐SIRT3+/+ and LA‐SIRT3−/− (37.0±4.4%, 38.2±4.4%). Endothelial‐independent relaxation (sodium nitroprusside) was also unchanged. MnSOD expression was reduced in LA‐SIRT3−/− compared to LA‐SIRT3+/+ (0.80 ± 0.02 vs 1.0±0.08, p < 0.05). In contrast, the late‐stage osteoblast marker, osterix, tended to increase in LA‐SIRT3−/− (1.3 fold) but failed to reach statistical significance. Collectively, these results suggest that losses of SIRT3 do not impact endothelial function in advanced atherosclerosis, but may contribute to augmentation of osteogenic signaling and accelerated progression of vascular calcification.