Midkine prevents ventricular remodeling and improves long-term survival after myocardial infarction.
Cardiac remodeling is thought to be the major cause of chronic heart dysfunction after myocardial infarction (MI). However, molecules involved in this process have not been thoroughly elucidated. In this study we investigated the long-term effects of the growth factor midkine (MK) in cardiac remodeling after MI. MI was produced by ligation of the left coronary artery. MK expression was progressively increased after MI in wild-type mice, and MK-deficient mice showed a higher mortality. Exogenous MK improved survival and ameliorated left ventricular dysfunction and fibrosis not only of MK-deficient mice but also of wild-type mice. Angiogenesis in the peri-infarct zone was also enhanced. These in vivo changes induced by exogenous MK were associated with the activation of phosphatidylinositol 3-kinase (PI3K)/Akt and MAPKs (ERK, p38) and the expression of syndecans in the left ventricular tissue. In vitro experiments using human umbilical vein endothelial cells confirmed the potent angiogenic action of MK via the PI3K/Akt pathway. These results suggest that MK prevents the cardiac remodeling after MI and improves the survival most likely through an enhancement of angiogenesis. MK application could be a new therapeutic strategy for the treatment of ischemic heart failure.
Takenaka
Hiroharu
H
Department of Biochemistry, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya, Japan.
Horiba
Mitsuru
M
Ishiguro
Hisaaki
H
Sumida
Arihiro
A
Hojo
Mayumi
M
Usui
Akihiko
A
Akita
Toshiaki
T
Sakuma
Sadatoshi
S
Ueda
Yuichi
Y
Kodama
Itsuo
I
Kadomatsu
Kenji
K
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D016207:Cytokines / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000078792:Midkine; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D053667:Syndecans / Q000378:metabolism; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D020257:Ventricular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D011994:Recombinant Proteins; D053667:Syndecans; D000078792:Midkine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases