Targeting antioxidants to mitochondria: a potential new therapeutic strategy for cardiovascular diseases.
Mitochondria produce large amounts of free radicals and play an important role in the life and death of a cell. Thus, mitochondrial oxidative damage and dysfunction contribute to a number of cell pathologies that manifest themselves through a range of conditions including ischemia-reperfusion injury, sepsis, diabetes, atherosclerosis and, consequently, cardiovascular diseases (CVD). In fact, endothelial dysfunction, characterized by a loss of nitric oxide (NO) bioactivity, occurs early on in the development of atherosclerosis, and determines future vascular complications. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are not yet clear, oxidative stress seems to play an important role. This review considers the process of CVD from a mitochondrial perspective. Accordingly, strategies for the targeted delivery of antioxidants to mitochondria are being developed. In this review, we will provide a summary of the following areas: the cellular metabolism of reactive oxygen species (ROS) and its role in pathophysiological processes such as CVD; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; recent developments in mitochondrially-targeted antioxidants that concentrate on the matrix-facing surface of the inner mitochondrial membrane and therefore protect against mitochondrial oxidative damage, and their therapeutic potential for future treatment of CVDs. More pre-clinical and clinical studies, however, are necessary in order to evaluate the effectiveness and toxicity of mitochondrially-targeted antioxidants.
Victor
V M
VM
Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernandez Almagro, 3, Madrid, Spain. vmvictor@cnic.es
Rocha
M
M
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000975:Antioxidants; D017382:Reactive Oxygen Species