New Strategies for Cardiovascular Gene Therapy: Regulatable Pre-Emptive Expression of Pro-Angiogenic and Antioxidant Genes

Abstract

Cardiovascular diseases are among the major targets for gene therapy. Initially, clinical experiments of gene transfer of vascular endothelial growth factor (VEGF) improved vascularization and prevented the amputation in patients with critical leg ischemia. However, the majority of trials did not provide conclusive results and therefore further preclinical studies are required. Importantly, data indicate the necessity of regulated expression of angiogenic factors, particularly VEGF, to obtain the therapeutic effect. It is also suggested that the combined delivery of two or more genes may improve the formation of mature vasculature and therefore may be more effective in the amelioration of ischemia. Moreover, experimental approaches in animal models displayed the promise of gene transfer modulating the inflammatory processes and oxidant status of the cells. Particularly, the concept of preemptive gene therapy has been tested, and recent studies have demonstrated that overexpression of heme oxygenase-1 or extracellular superoxide dismutase can prevent heart injury by myocardial infarction induced several weeks after gene instillation. The combination of a preemptive strategy with regulated gene expression, using the vectors in which the therapeutic transgene is driven by exogenously or endogenously controllable promoter, offers another modality. However, we hypothesize that regulatable gene therapy, dependent on the activity of endogenous factors, might be prone to limitations owing to the potential disturbance in the expression of endogenous genes. Here, we demonstrated some indications of these drawbacks. Therefore, the final acceptance of these promising strategies for clinical trials requires careful validation in animal experiments.

Cardiomyocyte-Specific Overexpression of NO Synthase-3 Protects Against Myocardial Ischemia-Reperfusion Injury

“…32 These studies revealed that the protection afforded by eNOS overexpression was NO dependent. Given the current interest [33][34][35] in translating gene therapy to the clinic, we sought to further clarify the protective effects of tissue-specific eNOS overexpression versus global overexpression. Using 2 distinct transgenic mice, we compared systemic versus tissue-specific (cardiomyocytespecific) eNOS overexpression.…”

NADPH Oxidases, Reactive Oxygen Species, and Hypertension

“…Therapeutic approaches that have been considered include mechanisms 1) to increase antioxidant capacity, 2) to increase NO bioavailability, and 3) to reduce ROS generation by decreasing activity of ⅐O 2 Ϫ -generating enzymes (121). Gene therapy targeting oxidant systems, such as NOS and hypoxia-inducible factor 1 (HIF-1) (122,123), are also being developed, but their use in clinical hypertension remains unclear.…”

Reactive oxygen species and vascular biology: implications in human hypertension

“…171,172 In fact Nox isoforms may be attractive therapeutic targets for vascular disease. [171][172][173] New peptide inhibitors that have been developed to specifically target NADPH oxidases include the 18 amino acid peptide gp91ds-tat, which interferes with Nox and subunit assembly, because nine of the amino acids mimic the region of p22phox that interacts with p47phox. 174 PR39, a naturally occurring 39 amino acid proline-and arginine-rich peptide that binds to Src homology domain 3 of p47phox also prevents association between p47phox and Nox, thereby inhibiting oxidase assembly and activation.…”