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1 Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
2 Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan
3 Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
4 Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan
5 Department of Pathology, National Cardiovascular Center, Suita, Osaka, Japan
6 Department of Cardiovascular Surgery, Okayama University Medical School, Okayama, Okayama, Japan
7 Department of Biochemistry, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
* To whom correspondence should be addressed. E-mail: nnagaya{at}ri.ncvc.go.jp.
Adrenomedullin (AM), a potent vasodilator, induces angiogenesis and inhibits cell apoptosis through the PI3K/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 106 cells) were injected into the ischemic myocardium, followed by subcutaneous administration of 0.05 µg/kg/min AM (AM-MNC group) or saline (MNC group) for three days. Another two groups of rats received subcutaneous administration of AM alone (AM group) or saline (Control group). Hemodynamic and histological analyses were performed four weeks 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 dP/dt 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 hours after transplantation, AM markedly decreased the number of TUNEL-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 anti-apoptotic effect on MNC.
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