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This Article Full Text Full Text (PDF) All Versions of this Article: 288/3/H1444    most recent 00266.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Fujii, T. Articles by Mori, H. Search for Related Content PubMed PubMed Citation Articles by Fujii, T. Articles by Mori, H.

Adrenomedullin enhances therapeutic potency of bone marrow transplantation for myocardial infarction in rats

Departments of ¹Cardiac Physiology, ²Regenerative Medicine and Tissue Engineering, ³Internal Medicine, ⁴Biochemistry, and ⁵Pathology, National Cardiovascular Center, Osaka; and ⁶Department of Cardiovascular Surgery, Okayama University Medical School, Okayama, Japan

Submitted 18 March 2004 ; accepted in final form 19 October 2004

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 10⁶ cells) were injected into the ischemic myocardium, followed by subcutaneous administration of 0.05 µg·kg^–1·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.

angiogenesis; apoptosis; mononuclear cell

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