pr-39 and Myocardial-Ischemia

Angiogenic therapy with individual growth factors or "master switch" genes is being evaluated for treatment of advanced coronary artery disease. In this study, we investigated the efficacy and mechanism of PR39, a gene capable of activating VEGF and fibroblast growth factor (FGF)-2-dependent pathways. PR39 enhances hypoxia-inducible factor-1alpha (HIF-1alpha)-dependent gene expression by selectively inhibiting proteasome degradation of this transcription factor. In addition, PR39 also stimulates expression of the FGF receptors (FGFR)-1 and syndecan-4. In a pig model of chronic myocardial ischemia, we used angiography, MRI, and microsphere regional blood flow to evaluate the efficacy of intramyocardial adenoviral protein arginine-rich peptide (Ad-PR39) injections. Ad-PR39 improved collateral scores, regional perfusion, and regional function in a dose-dependent manner. Local VEGF, VEGFR-1, VEGFR-2, syndecan, and FGFR-1 levels were 16-75% upregulated after Ad-PR39 injections as assessed by real-time PCR, suggesting upregulation of VEGF and FGF pathways. PR39 is an angiogenic peptide that improves perfusion and function of ischemic myocardium, at least in part, through collateral formation. The dual mechanism, i.e., stimulation of HIF-1alpha and FGF receptor expression, likely accounts for the functional benefits of PR39.

Topics: Adenoviridae; Angiogenic Proteins; Animals; Antimicrobial Cationic Peptides; Blood Flow Velocity; Chronic Disease; Coronary Circulation; Male; Myocardial Contraction; Myocardial Ischemia; Neovascularization, Physiologic; Recovery of Function; Swine; Treatment Outcome; Ventricular Dysfunction, Left; Viral Proteins

Although tissue injury and inflammation are considered essential for the induction of angiogenesis, the molecular controls of this cascade are mostly unknown. Here we show that a macrophage-derived peptide, PR39, inhibited the ubiquitin-proteasome-dependent degradation of hypoxia-inducible factor-1alpha protein, resulting in accelerated formation of vascular structures in vitro and increased myocardial vasculature in mice. For the latter, coronary flow studies demonstrated that PR39-induced angiogenesis resulted in the production of functional blood vessels. These findings show that PR39 and related compounds can be used as potent inductors of angiogenesis, and that selective inhibition of hypoxia-inducible factor-1alpha degradation may underlie the mechanism of inflammation-induced angiogenesis.

Topics: Animals; Antimicrobial Cationic Peptides; Aorta; Capillaries; Cattle; Cell Hypoxia; Cells, Cultured; Coronary Vessels; Cysteine Endopeptidases; DNA-Binding Proteins; Endothelium, Vascular; Heart; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; In Vitro Techniques; Macrophages; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multienzyme Complexes; Myocardial Infarction; Myocardial Ischemia; Neovascularization, Physiologic; Nuclear Proteins; Peptides; Proteasome Endopeptidase Complex; Recombinant Proteins; Swine; Transcription Factors; Ubiquitins; Umbilical Veins; von Willebrand Factor