Oxidative Stress and Endothelial Dysfunction in Cardiovascular Disease: Mitochondria-Targeted Therapeutics

M.      Rocha; N.      Apostolova; A.      Hernandez-Mijares; R.      Herance; V.      M. Victor

Abstract

Functional impairment of endothelial activity (endothelial dysfunction) precedes the development of cardiovascular diseases (CVD). This condition is a result of a reduced bioavailability of nitric oxide (NO), a well known vasodilator, which is mainly due to increased NO degradation caused by its reaction with reactive oxygen species (ROS). Although there are several conditions that contribute independently to endothelial dysfunction, such as hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia, increased oxidative stress seems to play a key role. In addition to their original pharmacological properties, drugs used clinically at present, including anti-hypertension reagents, angiotensin receptor blockers and anti-hyperlipidemic reagents such as statins, protect various organs via anti-oxidative stress mechanims. Moreover, some substances with antioxidant properties, such as vitamin C or vitamin E, have been used to erradicate the oxidative stress associated with CVD. The results of the clinical trials employing anti-oxidative stress reagents in patients with CVD are contradictory, which could be a result of inadequate study design or selected targets. This review considers the process of endothelial dysfunction and CVD from a mitochondrial perspective and evaluates strategies currently under development for the targeted delivery of antioxidants or NO to mitochondria. It endorses the idea that selectively targeting specific antioxidants and NO donors to mitochondria is an effective strategy for modulating mitochondrial respiration and ROS production and protecting mitochondria against oxidative stress.

Keywords: Antioxidant, cardiovascular dysfunction, endothelium, mitochondria, nitric oxide, oxidative stress, reactive oxygen species, endothelial dysfunction, cardiovas-cular diseases (CVD), bioavailability, reactive oxygen species (ROS), hyperglycemia, insu-lin resistance, hyperinsulinemia, dyslipidemia, angiotensin, vitamin C, vitamin E, endothelium, mitochondria, electron transport chain (ETC), atherosclerosis, endothelium-dependent vasodilatation, NITROGEN SPECIES (RONS), oxidative, fragmentation, lipid car-diolipin, glutathione peroxidases (GPx), metal-binding proteins, transferrin, lactoferrin, metal-lothionein, carotenoids, lipoic acid, tocopherols, N-acetyl cysteine (NAC), neuroprotective, Mitochondrial dysfunction, cell necrosis, neurodegenerative diseases, nitroglycerine, membrane depolarisation, cytochrome, synaptosomes, dyslipemia, obesity, antifibrinolitic, vasoconstrictor, proinflammatory, asymmetric dimethylargin-ine, hy-percholesterolemic, hydroxyocta-decaenoic acids (HODEs), hydroxyeicosatetraenoic acids (HETEs, The Probucol Quantitative Regression Study (PQRST), triphenylphosphonium (TPP), ubiquinol (MitoQ), S-Nitrosothiols (SNOs)