Adrenomedullin enhances therapeutic potency of bone marrow transplantation for myocardial infarction in rats.
Adrenomedullin (AM), a potent vasodilator, induces angiogenesis and inhibits cell apoptosis through the phosphatidylinositol 3-kinase/Akt pathway. Transplantation of bone marrow-derived mononuclear cells (MNC) induces angiogenesis. We investigated whether infusion of AM enhances the therapeutic potency of MNC transplantation in a rat model of myocardial infarction. Immediately after coronary ligation, bone marrow-derived MNC (5 x 10(6) cells) were injected into the ischemic myocardium, followed by subcutaneous administration of 0.05 microg x kg(-1) x min(-1) AM (AM-MNC group) or saline (MNC group) for 3 days. Another two groups of rats received subcutaneous administration of AM alone (AM group) or saline (control group). Hemodynamic and histological analyses were performed 4 wk after treatment. Cardiac infarct size was significantly smaller in the MNC and AM groups than in the control group. A combination of AM infusion and MNC transplantation demonstrated a further decrease in infarct size. Left ventricular (LV) maximum change in pressure over time and LV fractional shortening were significantly improved only in the AM-MNC group. AM significantly increased capillary density in ischemic myocardium, suggesting the angiogenic potency of AM. AM infusion plus MNC transplantation demonstrated a further increase in capillary density compared with AM or MNC alone. Although MNC apoptosis was frequently observed 72 h after transplantation, AM markedly decreased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells among the transplanted MNC. In conclusion, AM enhanced the angiogenic potency of MNC transplantation and improved cardiac function in rats with myocardial infarction. This beneficial effect may be mediated partly by the angiogenic property of AM itself and by its antiapoptotic effect on MNC.
Fujii
Takafumi
T
Department of Cardiac Physiology, National Cardiovascular Center, Suita, Osaka, Japan.
Nagaya
Noritoshi
N
Iwase
Takashi
T
Murakami
Shinsuke
S
Miyahara
Yoshinori
Y
Nishigami
Kazuhiro
K
Ishibashi-Ueda
Hatsue
H
Shirai
Mikiyasu
M
Itoh
Takefumi
T
Ishino
Kozo
K
Sano
Shunji
S
Kangawa
Kenji
K
Mori
Hidezo
H
D053607:Adrenomedullin; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation; D002196:Capillaries / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003131:Combined Modality Therapy; D003326:Coronary Circulation / Q000187:drug effects; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects*; D006352:Heart Ventricles / Q000473:pathology; D008297:Male; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009929:Organ Size; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D014665:Vasodilator Agents / Q000494:pharmacology*
D010455:Peptides; D014665:Vasodilator Agents; D053607:Adrenomedullin