Abstract 17135: Urotensin II Inhibited the Proliferation of Cardiac Side Population Cells in Mice During Pressure Overload by JNK-LRP6 Signaling
Cardiac side population cells (CSPs) are promising cell resource for the regeneration in diseased heart as intrinsic cardiac stem cells. However the relative low ratio of CSPs in the heart limited the ability of CSPs to repair heart and improve cardiac function effectively under pathophysiological condition. Which factors limit the proliferation of CSPs in diseased heart is unclear. Here, we show that urotensin II (UII) regulates the proliferation of CSPs by c-Jun N-terminal kinase (JNK) and low density lipoprotein receptor-related protein 6 (LRP6) signaling during pressure overload. Pressure overload was produced by the transverse aorta constriction (TAC) in 8-10- week C57BL6 mice. TAC greatly upregulated UII level in plasma. UII receptor (UT) antagonist, urantide, promoted CSPs proliferation and improved cardiac dysfunction after TAC for 4 weeks. In cultured CSPs subjected to mechanical stretch (MS), UII significantly inhibited the proliferation by UT. Nanofluidic proteomic immunoassay (NIA) showed it is the JNK activation, but not the extracellular signal-regulated kinas (ERK) signaling, that involved in the UII-inhibited- proliferation of CSPs during pressure overload. Further analysis in vitro indicated UII significantly suppressed the phosphorylation of LRP6 induced by MS in cultured CSPs, si-JNK or overexpression of LRP6 rescued the response and partly abolished the inhibitory effect of UII on the proliferation of CSPs during MS. In conclusion, UII inhibited the proliferation of CSPs by JNK-LRP6 signaling during pressure overload. Pharmacological inhibition of UII promotes CSPs proliferation in mice, offering a possible therapeutic approach for cardiac failure induced by pressure overload.
- © 2013 by American Heart Association, Inc.