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

Autor: Roos CM; Departments of Surgery, Mayo Clinic, Rochester, MN, USA., Zhang B; Departments of Surgery, Mayo Clinic, Rochester, MN, USA., Hagler MA; Departments of Surgery, Mayo Clinic, Rochester, MN, USA., Arghami A; Departments of Surgery, Mayo Clinic, Rochester, MN, USA., Miller JD; Departments of Surgery, Mayo Clinic, Rochester, MN, USA; Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, USA. Electronic address: miller.jordan@mayo.edu.
Jazyk: angličtina
Zdroj: Atherosclerosis [Atherosclerosis] 2021 Aug; Vol. 331, pp. 31-37. Date of Electronic Publication: 2021 Jun 08.
DOI: 10.1016/j.atherosclerosis.2021.06.005
Abstrakt: 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 100/100 ; 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. H 2 O 2 ). 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 H 2 O 2 . 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021. Published by Elsevier B.V.)
Databáze: MEDLINE
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