Issei Komuro
　　Department of Cardiovascular Medicine， Osaka University Graduate School of Medicine， Suita， Japan
　　Cardiac hypertrophy is developed as an adaptive response to increased workload. Although cardiac function first remains normal， prolonged cardiac hypertrophy causes heart failure. We have recently demonstrated that DNA damage of cardiomyocytes induces p53 accumulation and thus inhibition of angiogenesis， resulting in the transition from cardiac hypertrophy to heart failure. This result suggests that angiogenic therapy might be effective for heart failure.
　　We have treated over 100 "no-option" patients with critical limb ischemia by implantation of peripheral blood mononuclear cells. Cell therapy using peripheral blood mononuclear cells was very effective for ~70% of patients with limb ischemia， and its efficacy was associated with increases in plasma levels of angiogenic factors. Implantation of the cells induced regeneration of skeletal muscle and activated satellite cells produced various kinds of angiogenic growth factors， thereby promoting neovascularization in ischemic tissues. We have recently found that implantation of peripheral blood mononuclear cells into heart is also effective to improve cardiac ischemia.
　　We have identified a novel cardiomyocyte differentiation factor， IGFBP-4.  IGFBP-4 enhanced cardiomyocyte differentiation in vitro， and knockdown of Igfbp4 attenuated cardiomyogenesis both in vitro and in vivo. The cardiogenic effect of IGFBP-4 was independent of its IGF-binding activity but was mediated by the inhibitory effect on canonical Wnt signalling. We previously found that leukemia inhibitory factor (LIF) protected heart from myocardial infarction at lease by prevention of cardiomyocyte death and angiogenesis.  Recently， we have established a novel system to dissect cardiac regeneration and found that LIF also induces formation of new cardiomyocytes.
　　Minamino T， Komuro I et al.  Peripheral-blood or bone-marrow mononuclear cells for therapeutic angiogenesis?  Lancet 360:2083-2084， 2002.
　　Zou Y， Komuro I et al.  Leukemia Inhibitory Factor Enhances Survival of Cardiomyocytes and Induces Regeneration of Myocardium After Myocardial Infarction.  Circulation 108:748-753， 2003.
　　Sano M， Komuro I et al.  p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload.  Nature 446:444-448， 2007
　　Zhu W， Komuro I. et al. IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis.  Nature. 454:345-349， 2008