A synthetic small molecule, ONO-1301, enhances endogenous growth factor expression and augments angiogenesis in the ischaemic heart.
It has been shown previously that administration of angiogenic growth factors as genes or proteins can augment collateral growth in ischaemic tissues. In the present study, we have investigated the effect of ONO-1301, a synthetic prostacyclin agonist with thromboxane-synthase-inhibitory activity, on expression of endogenous growth factors and angiogenesis. ONO-1301 induced secretion of HGF (hepatocyte growth factor) and VEGF (vascular endothelial growth factor) from cultured normal human dermal fibroblasts in a dose-dependent manner. Dibutyryl cAMP, an analogue of cAMP, and forskolin, an adenylate cyclase activator, mimicked the effect of ONO-1301. Conversely, Rp-cAMP (adenosine 3',5'-cyclic monophosphorothioate), an inhibitor of cAMP, partially inhibited the effect of ONO-1301, suggesting that cAMP mediated the effect of ONO-1301 in up-regulating the expression of HGF and VEGF, at least in part. ONO-1301 promoted tube-like formation by HUVECs (human umbilical vein endothelial cells) when co-cultured with fibroblasts, and the angiogenic effect of ONO-1301 was abrogated by administration of a neutralizing antibody against HGF or VEGF. To generate a slow-releasing form of ONO-1301, ONO-1301 was mixed with poly(DL-lactic-co-glycolic acid). The slow-releasing form of ONO-1301 was injected directly into the ischaemic myocardium of mice immediately after ligation of the left anterior descending artery. The slow-releasing form of ONO-1301 up-regulated HGF and VEGF expression and increased capillary density in the border zone (342.7+/-29.7 capillaries/mm(2) in controls compared with 557.2+/-26.7 capillaries/mm(2) in treated animals; P<0.01) at 7 days. The slow-releasing form of ONO-1301 ameliorated left ventricular enlargement after 28 days and improved survival rate. In conclusion, our results indicate that ONO-1301 up-regulated endogenous growth factors and promoted angiogenesis in response to acute ischaemia. Therefore ONO-1301 might have a therapeutic potential in treating ischaemic diseases.
Nakamura
Kazuto
K
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan.
Sata
Masataka
M
Iwata
Hiroshi
H
Sakai
Yoshiki
Y
Hirata
Yasunobu
Y
Kugiyama
Kiyotaka
K
Nagai
Ryozo
R
D000818:Animals; D004108:Dilatation, Pathologic; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000819:agonists; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000032:analysis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000378:metabolism
D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C105488:ONO 1301; D017228:Hepatocyte Growth Factor; D011464:Epoprostenol; D013930:Thromboxane-A Synthase