Overexpression of MnSOD Does Not Improve Endothelial Function in Hypercholesterolemic Mice

Abstract

We previously reported that MnSOD‐deficiency does not cause overt vasomotor dysfunction in aged or hypercholesterolemic mice. To determine whether increasing MnSOD protects against vasomotor dysfunction and deleterious molecular changes in atherosclerosis, we crossed hypercholesterolemic mice with mice overexpressing MnSOD to test the hypothesis that lifelong increases in MnSOD protect against vasomotor dysfunction. We used Ldlr‐/‐/ApoB100/100 mice that were wild‐type (MnSOD0/0) or transgenic (MnSODTg/0) and fed a western diet for 6 months. We used organ bath chambers to measure aortic endothelium‐dependent relaxation (relaxation to acetylcholine, Ach), and mRNA from aortic arch was used for qRT‐PCR. Surprisingly, relaxation to Ach was unchanged between MnSOD0/0 and MnSODTg/0 mice, as was relaxation to sodium nitroprusside. As expected, gene expression of MnSOD was significantly increased in the MnSODTg/0 mice compared to MnSOD0/0 mice. Unlike our findings in MnSOD+/‐ mice, however (where Nox2 was increased), Nox2 expression was unchanged between MnSOD0/0 and MnSODTg/0 mice. Importantly, markers of osteogenesis such as Runx2 and BMP2 were unchanged between genotypes. Furthermore, MnSOD overexpression did not alter cellular senescence markers. Collectively, our data support the surprising conclusion that physiologically relevant increases in MnSOD do not significantly affect endothelial function or molecular regulators of histopathological changes in advanced atherosclerosis in hypercholesterolemic mice.