MnSOD protects against vascular calcification independent of changes in vascular function in hypercholesterolemic mice.

BACKGROUND AND AIMS

The overall goal of this study was to determine the effects of MnSOD-deficiency on vascular structure and function in hypercholesterolemic mice. Previous work suggested that increases in mitochondrial-derived reactive oxygen species (ROS) can exacerbate vascular dysfunction and atherosclerosis. It remains unknown, however, how MnSOD-deficiency and local compensatory mechanisms impact atherosclerotic plaque composition.

METHODS AND RESULTS

We used a hypercholesterolemic mouse model (ldlr/ApoB; LA), either wild-type for MnSOD (LA-MnSOD) or MnSOD-haploinsufficient (LA-MnSOD), that was fed a western diet for either 3 or 6 months. Consistent with previous reports, reductions of MnSOD did not significantly worsen hypercholesterolemia-induced endothelial dysfunction in the aorta. Critically, dramatic impairment of vascular function with Nox2 inhibition or catalase pretreatment suggested the presence of a significant NO-independent vasodilatory mechanism in LA-MnSOD mice (e.g. HO). Despite remarkably well-preserved overall vascular relaxation, loss of mitochondrial antioxidant capacity in LA-MnSOD mice significantly increased osteogenic signalling and vascular calcification compared to the LA-MnSOD littermates.

CONCLUSIONS

Collectively, these data are the first to suggest that loss of mitochondrial antioxidant capacity in hypercholesterolemic mice results in dramatic upregulation of NADPH oxidase-derived HO. While this appears to be adaptive in the context of preserving overall endothelium-dependent relaxation and vascular function, these increases in ROS appear to be remarkably maladaptive and deleterious in the context of vascular calcification.