Cardiomyocyte-specific overexpression of human stem cell factor protects against myocardial ischemia and reperfusion injury.

Abstract

BACKGROUND:

Cardiomyocyte-specific overexpression of human membrane-associated stem cell factor (hSCF) improves cardiac function post-myocardial infarction. However, whether hSCF overexpression protects the heart from ischemia and reperfusion (I/R) injury is unknown. We aimed to investigate the effects of cardiomyocyte-specific overexpression of hSCF on cardiac injury after acute myocardial I/R and related cellular and molecular signaling mechanisms.

METHODS AND RESULTS:

Wild-type (WT) and hSCF/tetracycline transactivator (tTA) transgenic mice (hSCF/tTA) were subjected to myocardial ischemia for 45 min followed by 3 h of reperfusion. Infarct size and myocardial apoptosis were decreased in hSCF/tTA compared to WT mice (P<0.05). Furthermore, these cardioprotective effects in the hSCF/tTA mice were abrogated by doxycycline, which turned off hSCF overexpression, and by a PI3 kinase inhibitor LY294002. Myocardial expression of insulin-like growth factor (IGF)-1 and hepatocyte growth factor (HGF), which are upstream activators of Akt signaling, was significantly increased in hSCF/tTA compared to WT mice after I/R (P<0.05), and was associated with higher number of c-kit(+) cardiac stem cells (CSCs) (P<0.05). Inhibition of c-kit signaling by ACK2 treatment abolished these protective effects in hSCF/tTA mice.

CONCLUSIONS:

Cardiomyocyte-specific overexpression of hSCF protects the heart from I/R injury. The cardioprotective effects of hSCF overexpression are mediated by increased c-kit(+) CSCs, enhanced growth factor expression and activation of Akt signaling pathway.

• Authors: Fu-Li Xiang, Xiangru Lu, Yin Liu, Qingping Feng
• Journal: International journal of cardiology (Int J Cardiol) Vol. 168 Issue 4 Pg. 3486-94 (Oct 09 2013) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 23680593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Cardiotonic Agents
• Stem Cell Factor

Topics

• Animals
• Cardiotonic Agents (metabolism)
• Gene Expression Regulation
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Mice, Transgenic
• Myocardial Ischemia (genetics, metabolism, prevention & control)
• Myocardial Reperfusion Injury (genetics, metabolism, prevention & control)
• Myocytes, Cardiac (metabolism, pathology)
• Stem Cell Factor (biosynthesis, genetics)