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

Carolyn M. Roos, Bin Zhang, Michael A. Hagler, Arman Arghami, Jordan D. Miller

Research output: Contribution to journalArticlepeer-review


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−/−/ApoB100/100; 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. H2O2). 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 H2O2. 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.

Original languageEnglish (US)
Pages (from-to)31-37
Number of pages7
StatePublished - Aug 2021


  • Atherosclerosis
  • Mitochondria
  • Oxidative stress
  • Vascular calcification
  • Vascular function

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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