SIRT3 Inactivation Impairs Endothelial Function and Promotes Vascular Calcification in Hypercholesterolemic Mice

Recent work by other investigators have shown that SIRT3 is an important regulator of endothelial function in obese patients or animals, as reductions in SIRT3 drive increased mitochondrial ROS (mtROS) production. The role of SIRT3 in atherosclerotic mice, however, remains unclear. Therefore, we hypothesized genetic inactivation of SIRT3 in hypercholesterolemic mice will impair vascular function, reduce antioxidant gene expression, and increase pro‐osteogenic signaling. We used Ldlr −⁄− /ApoB 100/100 mice that were either wild‐type (LA‐SIRT3 +/+ ) or null for SIRT3 (LA‐SIRT3 −⁄− ). After 12 weeks of western diet feeding, we assessed endothelial function of aorta using isolated organ bath chambers and measured changes in gene expression using qRT‐PCR. Consistent with our hypothesis, loss of SIRT3 significantly impaired relaxation to acetylcholine (Ach) (LA‐SIRT3 −⁄− : 48.2%±3.0, LA‐SIRT3 +/+ : 57.6%±1.7). Incubation with Mito‐Tempol significantly improved endothelial‐dependent relaxation in LA‐SIRT3 −⁄− mice (57.0%±2.9), but not in LA‐SIRT3 +/+ mice. Interestingly, losses of SIRT3 did not alter expression of MnSOD, ecSOD, or CuZnSOD. Gene expression of the late‐stage osteoblast marker, osterix, tended to be increased in LA‐SIRT3 −⁄− mice compared to wild‐type mice (p = 0.06). Collectively, losses of SIRT3 impair endothelial function and tend to increase osteogenic signaling in severe hypercholesterolemia. Importantly, these functional and molecular changes and may result from increased mtROS, which may serve as a viable therapeutic target to slow pathological processes during progression of atherosclerosis. Support or Funding Information NHLBI R01‐HL111121