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

Atherosclerosis. 2021 Aug:331:31-37. doi: 10.1016/j.atherosclerosis.2021.06.005. Epub 2021 Jun 8.

Abstract

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.

Keywords: Atherosclerosis; Mitochondria; Oxidative stress; Vascular calcification; Vascular function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Hydrogen Peroxide*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria
  • Oxidative Stress
  • Reactive Oxygen Species
  • Superoxide Dismutase
  • Vascular Calcification* / genetics
  • Vascular Calcification* / prevention & control
  • Vasodilation

Substances

  • Reactive Oxygen Species
  • Hydrogen Peroxide
  • Superoxide Dismutase