Departments of Surgery, Mayo Clinic, Rochester, MN, USA.
Departments of Surgery, Mayo Clinic, Rochester, MN, USA; Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
Atherosclerosis. 2021 Aug;331:31-37. doi: 10.1016/j.atherosclerosis.2021.06.005. Epub 2021 Jun 8.
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.
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.
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.
本研究的总体目标是确定 MnSOD 缺乏对高胆固醇血症小鼠血管结构和功能的影响。先前的工作表明，线粒体来源的活性氧（ROS）的增加会加剧血管功能障碍和动脉粥样硬化。然而，MnSOD 缺乏和局部代偿机制如何影响动脉粥样硬化斑块的组成仍不清楚。
我们使用了一种高胆固醇血症小鼠模型（ldlr/ApoB；LA），该模型要么是 MnSOD 野生型（LA-MnSOD），要么是 MnSOD 半缺陷型（LA-MnSOD），喂食西方饮食 3 或 6 个月。与之前的报告一致，MnSOD 的减少并没有显著加重高胆固醇血症诱导的主动脉内皮功能障碍。重要的是，Nox2 抑制或过氧化氢酶预处理引起的血管功能急剧损害表明，LA-MnSOD 小鼠存在显著的非一氧化氮依赖性血管舒张机制（例如 HO）。尽管整体血管舒张功能得到了显著的保护，但 LA-MnSOD 小鼠线粒体抗氧化能力的丧失与 LA-MnSOD 同窝小鼠相比，显著增加了成骨信号和血管钙化。
综上所述，这些数据首次表明，高胆固醇血症小鼠中线粒体抗氧化能力的丧失导致 NADPH 氧化酶衍生的 HO 显著上调。虽然这在保持整体内皮依赖性舒张和血管功能方面似乎是适应性的，但这些 ROS 的增加在血管钙化方面似乎是非常不适宜和有害的。
