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Am J Physiol Regul Integr Comp Physiol 290: R494-R500, 2006. First published October 27, 2005; doi:10.1152/ajpregu.00460.2005
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Angiogenesis in Health and Disease

Adenoviral PR39 improves blood flow and myocardial function in a pig model of chronic myocardial ischemia by enhancing collateral formation

Mark J. Post,1,3 Kaori Sato,2 Masahiro Murakami,1 Jialin Bao,2 Daniela Tirziu,1 Justin D. Pearlman,1 and Michael Simons1

1Angiogenesis Research Center and Section of Cardiology, Dartmouth Medical School, Lebanon, New Hampshire; 2Beth Israel Deaconess Medical Center, Boston, Massachusetts; and 3Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

Submitted 29 June 2005 ; accepted in final form 17 October 2005

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-1{alpha} (HIF-1{alpha})-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-1{alpha} and FGF receptor expression, likely accounts for the functional benefits of PR39.

angiogenesis; growth factors; hypoxia-inducible factor-1{alpha}


Address for reprint requests and other correspondence: M. J. Post, Dept. of Physiology, Maastricht Univ., Universiteitssingel 50, 6229 ER Maastricht, The Netherlands (e-mail: m.post{at}fys.unimaas.nl)




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