Kim Kyoungrae, Anderson Erik M, Scali Salvatore T, Ryan Terence E
Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, USA.
Division of Vascular Surgery and Endovascular Therapy, University of Florida, Gainesville, FL 32611, USA.
Antioxidants (Basel). 2020 Dec 18;9(12):1304. doi: 10.3390/antiox9121304.
Peripheral artery disease (PAD) is caused by atherosclerosis in the lower extremities, which leads to a spectrum of life-altering symptomatology, including claudication, ischemic rest pain, and gangrene requiring limb amputation. Current treatments for PAD are focused primarily on re-establishing blood flow to the ischemic tissue, implying that blood flow is the decisive factor that determines whether or not the tissue survives. Unfortunately, failure rates of endovascular and revascularization procedures remain unacceptably high and numerous cell- and gene-based vascular therapies have failed to demonstrate efficacy in clinical trials. The low success of vascular-focused therapies implies that non-vascular tissues, such as skeletal muscle and oxidative stress, may substantially contribute to PAD pathobiology. Clues toward the importance of skeletal muscle in PAD pathobiology stem from clinical observations that muscle function is a strong predictor of mortality. Mitochondrial impairments in muscle have been documented in PAD patients, although its potential role in clinical pathology is incompletely understood. In this review, we discuss the underlying mechanisms causing mitochondrial dysfunction in ischemic skeletal muscle, including causal evidence in rodent studies, and highlight emerging mitochondrial-targeted therapies that have potential to improve PAD outcomes. Particularly, we will analyze literature data on reactive oxygen species production and potential counteracting endogenous and exogenous antioxidants.
外周动脉疾病（PAD）由下肢动脉粥样硬化引起，会导致一系列改变生活的症状，包括间歇性跛行、缺血性静息痛以及需要截肢的坏疽。目前针对PAD的治疗主要集中于恢复缺血组织的血流，这意味着血流是决定组织能否存活的决定性因素。不幸的是，血管内治疗和血管重建手术的失败率仍然高得令人无法接受，并且许多基于细胞和基因的血管治疗在临床试验中未能证明其疗效。以血管为重点的治疗成功率较低，这意味着非血管组织，如骨骼肌和氧化应激，可能在PAD病理生物学中起重要作用。骨骼肌在PAD病理生物学中的重要性线索源于临床观察，即肌肉功能是死亡率的有力预测指标。尽管对其在临床病理学中的潜在作用尚未完全了解，但已在PAD患者中记录到肌肉中的线粒体损伤。在本综述中，我们讨论了导致缺血性骨骼肌线粒体功能障碍的潜在机制，包括啮齿动物研究中的因果证据，并强调了有潜力改善PAD治疗结果的新兴线粒体靶向治疗。特别是，我们将分析有关活性氧产生以及潜在的内源性和外源性抗氧化剂抵消作用的文献数据。
