Mitochondrially Targeted Antioxidants for the Treatment of Cardiovascular Diseases

Abstract

Oxidative stress resulting from imbalance between reactive oxygen species (ROS) generation and antioxidant mechanisms is important in the pathogenesis of cardiovascular diseases such as atherosclerosis, ischemic heart disease, heart failure, stroke, hypertension and diabetes. Paradoxically, antioxidant therapy such as vitamin E has not been shown on large randomized clinical trials to favorably affect clinical outcomes. Since mitochondria are involved not only with bioenergetics but also with oxidative damage through ROS generation and cell signaling leading to apoptosis, antioxidants targeted at the mitochondria are appealing novel agents to attenuate oxidative stress. In particular, antioxidants conjugated with triphenylphosphonium cation such as mitoquinone, mitovitamin E and mitophenyltertbutyline achieve concentrations in the mitochondrial matrix several-fold greater than those achieved in the cytosol because of the high negative membrane potential of the inner mitochondrial membrane. We review preliminary experiments and also some patents on cell and animal models of cardiovascular diseases where mitochondrially targeted antioxidants have been used and were shown to reduce ROS production and the effects of oxidative stress due to ROS, apoptosis and improve cardiac function. Although ongoing human clinical studies involve only non-cardiovascular applications at this time, preclinical studies show promise for eventual human trials for cardiovascular diseases.

Mitochondria-targeted agents: Future perspectives of mitochondrial pharmaceutics in cardiovascular diseases

“…Mitochondrial oxidative stress resulting from an imbalance between the generation of ROS and the existing mitochondrial antioxidant mechanisms has been described in the pathogenesis of CVDs, including HF [27] . HF followed by MI can be initiated with the mitochondrial damage and dysfunction that can be ascribed to: (1) increased lipid peroxidation; (2) reduced mitochondrial gene replication, mtDNA copy number and mitochondrial gene transcription; and (3) reduced OXPHOS due to low respiratory chain complex enzyme activities ( Figure 5).…”

Oxidative stress – assassin behind the ischemic stroke

“…This emphasises that the molecular mechanisms of ROS signalling after stroke are not fully understood. Since mitochondria are a major player in the ischemic cascade, antioxidants targeted at the organelle are being developed to reduce oxidative stress [78]. The use of recognised antioxidants like vitamin E and C as dietary supplements to reduce the risk of stroke is also being investigated [37].…”

The Protective Role of Alpha Lipoic Acid on Organ Damages Induced by Oxidative Stress

“…Antioxidants such as ALA are widely regarded as attractive novel agents which can be employed to prevent oxidative stress. [22] Several studies have reported that ALA administration effectively decreases the cardiac apoptosis. [23,24] …”