Adenoviral PR39 improves blood flow and myocardial function in a pig model of chronic myocardial ischemia by enhancing collateral formation.
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.
Post
Mark J
MJ
Angiogenesis Research Center and Section of Cardiology, Dartmouth Medical School, Lebanon, New Hampshire, USA. m.post@fys.unimaas.nl
Sato
Kaori
K
Murakami
Masahiro
M
Bao
Jialin
J
Tirziu
Daniela
D
Pearlman
Justin D
JD
Simons
Michael
M
D000256:Adenoviridae / Q000378:metabolism; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000627:therapeutic use*; D001783:Blood Flow Velocity / Q000187:drug effects; D002908:Chronic Disease; D003326:Coronary Circulation / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D020127:Recovery of Function / Q000187:drug effects; D013552:Swine; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D014764:Viral Proteins / Q000627:therapeutic use
D042501:Angiogenic Proteins; D023181:Antimicrobial Cationic Peptides; D014764:Viral Proteins; C072212:PR 39