Urotensin II inhibited the proliferation of cardiac side population cells in mice during pressure overload by JNK-LRP6 signalling.
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 limiting the proliferation of CSPs in diseased heart are 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) signalling during pressure overload. Pressure overload greatly upregulated UII level in plasma, UII receptor (UT) antagonist, urantide, promoted CSPs proliferation and improved cardiac dysfunction during chronic pressure overload. In cultured CSPs subjected to mechanical stretch (MS), UII significantly inhibited the proliferation by UT. Nanofluidic proteomic immunoassay showed that it is the JNK activation, but not the extracellular signal-regulated kinase signalling, that involved in the UII-inhibited- proliferation of CSPs during pressure overload. Further analysis in vitro indicated UII-induced-phospho-JNK regulates phosphorylation of LRP6 in cultured CSPs after MS, which is important in the inhibitory effect of UII on the CSPs during pressure overload. In conclusion, UII inhibited the proliferation of CSPs by JNK/LRP6 signalling during pressure overload. Pharmacological inhibition of UII promotes CSPs proliferation in mice, offering a possible therapeutic approach for cardiac failure induced by pressure overload.
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Zhidan
Z
Chen
Jiahong
J
Xu
Yong
Y
Ye
Yang
Y
Li
Hui
H
Gong
Guoping
G
Zhang
Jian
J
Wu
Jianguo
J
Jia
Ming
M
Liu
Ying
Y
Chen
Chunjie
C
Yang
Yu
Y
Tang
Yichun
Y
Zhu
Junbo
J
Ge
Yunzeng
Y
Zou
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology*; D010446:Peptide Fragments; D010766:Phosphorylation / Q000187:drug effects; D011312:Pressure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D058985:Side-Population Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects*; D013314:Stress, Mechanical; D014579:Urotensins / Q000097:blood / Q000494:pharmacology*
D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D014579:Urotensins; C492079:urotensin II (4-11), Pen(5)-Trp(7)-Orn(8)-; C029677:urotensin II; D048031:JNK Mitogen-Activated Protein Kinases
CSPs; JNK; LRP6; Urotensin II; proliferation