There is currently intense interest in the development of gene therapy for
cardiovascular disease. The stimulation of therapeutic angiogenesis for
ischemic heart disease has been one of the areas of greatest promise. Encouraging results have been obtained with the angiogenic
cytokines vascular endothelial growth factor (
VEGF) and
basic fibroblast growth factor in animal models, leading to clinical trials in
ischemic heart disease.
VEGF also has therapeutic potential in a second area of cardiovascular gene therapy, the enhancement of arterioprotective endothelial functions to prevent postangioplasty restenosis and bypass graft arteriopathy. The endothelial cell growth and survival functions of
VEGF promote endothelial regeneration, whereas
VEGF-induced endothelial production of NO and
prostacyclin inhibits vascular smooth muscle cell proliferation. Inhibition of neointimal
hyperplasia may also be achieved by gene transfer of endothelial
NO synthase (eNOS), PGI synthase, or cell cycle regulators (
retinoblastoma,
cyclin or
cyclin-dependent kinase inhibitors, p53, growth arrest homeobox gene,
fas ligand) or
antisense oligonucleotides to c-myb, c-myc,
proliferating cell nuclear antigen, and
transcription factors such as
nuclear factor kappaB and E2F. An improved understanding of etiologically complex pathologies involving the interplay of genes and the environment, such as
atherosclerosis and systemic
hypertension, has led to the identification of new targets for gene therapy, with the potential to alleviate inherited genetic defects such as
familial hypercholesterolemia. The use of
vasodilator gene overexpression and antisense knockdown of
vasoconstrictors to reduce blood pressure in animal models of systemic and
pulmonary hypertension offers the prospect of gene therapy for human hypertensive disease. The renin-angiotensin system has been the target of choice for
antihypertensive strategies because of its wide distribution and additional effects on fibrinolytic and oxidative stress pathways. Gene therapy in
cardiovascular disease has an exciting future but remains at an early stage. Further developments in gene transfer vector technology and the identification of additional target genes will be required before its full therapeutic potential can be realized.