The School of Health and Kinesiology, University of Nebraska- Omaha, Omaha, NE, USA.
Geriatric Research, Education, and Clinical Center, George E. Whalen VA Medical Center, Salt Lake City, UT, USA.
Acta Physiol (Oxf). 2018 Jan;222(1). doi: 10.1111/apha.12893. Epub 2017 Jun 8.
This study sought to determine the role of free radicals derived from mitochondria in the vasculature in the recognized age-related endothelial dysfunction of human skeletal muscle feed arteries (SMFAs).
A total of 44 SMFAs were studied with and without acute exposure to the mitochondria-targeted antioxidant MitoQ and nitric oxide synthase (NOS) blockade. The relative abundance of proteins from the electron transport chain, phosphorylated (p-) to endothelial (e) NOS ratio, manganese superoxide dismutase (MnSOD) and the mitochondria-derived superoxide (O2-) levels were assessed in SMFA. Endothelium-dependent and endothelium-independent SMFA vasodilation was assessed in response to flow-induced shear stress, acetylcholine (ACh) and sodium nitroprusside (SNP).
MitoQ restored endothelium-dependent vasodilation in the old to that of the young when stimulated by both flow (young: 68 ± 5; old: 25 ± 7; old + MitoQ 65 ± 9%) and ACh (young: 97 ± 4; old: 59 ± 10; old + MitoQ: 98 ± 5%), but did not alter the initially uncompromised, endothelium-independent vasodilation (SNP). Compared to the young, MitoQ in the old diminished the initially elevated mitochondria-derived O2- levels and appeared to attenuate the breakdown of MnSOD. Furthermore, MitoQ increased the ratio of p-eNOS to NOS and the restoration of endothelium-dependent vasodilation in the old by MitoQ was ablated by NOS blockade.
This study demonstrated that MitoQ reverses age-related vascular dysfunction by what appears to be an NO-dependent mechanism in human SMFAs. These findings suggest that mitochondria-targeted antioxidants may have utility in terms of counteracting the attenuated blood flow and vascular dysfunction associated with advancing age.
本研究旨在确定线粒体衍生自由基在血管中的作用，以认识到人类骨骼肌营养动脉（SMFA）的与年龄相关的内皮功能障碍。
共研究了 44 条 SMFA，分别在急性暴露于靶向线粒体的抗氧化剂 MitoQ 和一氧化氮合酶（NOS）阻断的情况下进行了研究。评估了 SMFA 中电子传递链的蛋白质相对丰度、磷酸化（p-）内皮（e）NOS 比值、锰超氧化物歧化酶（MnSOD）和线粒体衍生的超氧化物（O2-）水平。通过血流诱导的切应力、乙酰胆碱（ACh）和硝普钠（SNP）评估 SMFA 的内皮依赖性和非内皮依赖性血管舒张。
MitoQ 使老年 SMFA 对血流（年轻：68±5；老年：25±7；老年+MitoQ：65±9%）和 ACh（年轻：97±4；老年：59±10；老年+MitoQ：98±5%）刺激的内皮依赖性血管舒张恢复到年轻水平，但不改变最初未受损的内皮非依赖性血管舒张（SNP）。与年轻组相比，MitoQ 使老年组中最初升高的线粒体衍生 O2-水平降低，并且似乎减轻了 MnSOD 的破坏。此外，MitoQ 增加了 p-eNOS 与 NOS 的比值，并且 MitoQ 恢复老年内皮依赖性血管舒张的作用被 NOS 阻断所消除。
本研究表明，MitoQ 通过一种似乎依赖于 NO 的机制逆转了人类 SMFA 中与年龄相关的血管功能障碍。这些发现表明，靶向线粒体的抗氧化剂可能在对抗与年龄相关的血流减少和血管功能障碍方面具有实用性。
