Midkine prevents ventricular remodeling and improves long-term survival after myocardial infarction

Hiroharu Takenaka, Mitsuru Horiba, Hisaaki Ishiguro, Arihiro Sumida, Mayumi Hojo, Akihiko Usui, Toshiaki Akita, Sadatoshi Sakuma, Yuichi Ueda, Itsuo Kodama, Kenji Kadomatsu

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)H462-H469
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume296
Issue number2
DOIs
Publication statusPublished - 02-2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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