Antioxidant Gene Therapy for Cardiovascular Disease

Abstract

Abstract-Excessive production of reactive oxygen species has been implicated to play an important role in a number of cardiovascular pathologies, including hypertension, atherosclerosis, myocardial infarction, ischemia/reperfusion injury, and restenosis after angioplasty or venous bypass grafting. The formation of reactive oxygen species is balanced out by antioxidant defenses, and augmenting this defense by antioxidant therapies could therefore provide a potential means to treat conditions in which the formation of reactive oxygen species exceeds the capability of natural protective mechanisms. In this review, we summarize the studies in which antioxidant gene therapy has been used successfully to treat cardiovascular diseases. We also discuss the current limitations of antioxidant gene therapy and envision future therapeutic targets and methodological approaches for an improved outcome. (Circulation. 2008;117:2142-2150.)

Oxidative stress-inducible lentiviral vectors for gene therapy

“…[1][2][3] Counterbalancing the effects of ROS using antioxidant gene transfer for therapy has been shown to be effective in several experimental animal models of cardiovascular pathologies associated with increased radical production. 3 Transfer of therapeutic genes with traditional gene therapy vectors brings on continuous expression of genes, which may be disadvantageous when antioxidant genes are concerned, as ROS mediate also physiological cell signaling processes. 3,26 Regulatable vectors offer a solution to this problem, especially if they can be regulated by endogenous stimuli relevant to the pathology.…”

“…3 Transfer of therapeutic genes with traditional gene therapy vectors brings on continuous expression of genes, which may be disadvantageous when antioxidant genes are concerned, as ROS mediate also physiological cell signaling processes. 3,26 Regulatable vectors offer a solution to this problem, especially if they can be regulated by endogenous stimuli relevant to the pathology. Hypoxiaactivated adeno-associated virus (AAV) vector-expressing HO-1 has been developed and successfully used for treatment of cardiac I/R injury, 10 and HO-1 gene transfer also offers protection against chronic recurrent I/R injury and prevents post-infarction heart failure.…”

“…Of note, several antioxidant genes such as extracellular superoxide dismutase and heme oxygenase-1 (HO-1) have been used for gene therapy in experimental animal models of CVD. 3 Heme oxygenase-1 has well-documented protective effects in the vasculature (reviewed in Stocker and Perrella 4 and Ryter et al 5 ). It is the rate-limiting enzyme of heme catabolism, in which heme is degraded to carbon monoxide (CO) and biliverdin.…”

“…3,6 Both of these can exert their effects in the vasculature through multiple mechanisms (for example, by inhibition of vascular smooth muscle proliferation, promotion of vessel relaxation and inhibition of inflammation). Overexpression of HO-1 or the administration of CO is anti-inflammatory via suppression of proinflammatory cytokines and promotion of the expression of the anti-inflammatory interleukin-10.…”

Enzymatic Antioxidants: Next Phase of Pharmacological Effort to Fight Oxidative Stress?

“…The notable interest of researches to EC-SOD [16,17,[20][21][22][23][24][25][26][27][28] that is the (SOD-3) tetramer of Cu,Zn-SOD with high affinity to heparan sulphate [29][30][31] in the mammals, or its dimer form of Cu,Zn-SOD with low affinity to heparan sulphate [16,29,31] in the rats (as a result, the rats represent actually almost physiological knocked-out model for this enzyme) caused the development of gene therapy approaches aimed at ensuring antioxidant activity of the organism due to transfer of the appropriate genes [10,32]. Antioxidant gene therapy proved to be successful in experimental models of restenosis (rabbits, rats, pigs, etc.)…”