p27 kip1 haplo-insufficiency improves cardiac function in early-stages of myocardial infarction by protecting myocardium and increasing angiogenesis by promoting IKK activation

Ningtian Zhou; Yuxuan Fu; Yunle Wang; Pengsheng Chen; Haoyu Meng; Shouyu Guo; Min Zhang; Zhijian Yang; Yingbin Ge

doi:10.1038/srep05978

p27 kip1 haplo-insufficiency improves cardiac function in early-stages of myocardial infarction by protecting myocardium and increasing angiogenesis by promoting IKK activation

Sci Rep. 2014 Aug 7:4:5978. doi: 10.1038/srep05978.

Authors

Ningtian Zhou¹, Yuxuan Fu², Yunle Wang¹, Pengsheng Chen¹, Haoyu Meng¹, Shouyu Guo¹, Min Zhang¹, Zhijian Yang¹, Yingbin Ge²

Affiliations

¹ Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
² Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China.

Abstract

p27(kip1) (p27) is widely known as a potent cell cycle inhibitor in several organs, especially in the heart. However, its role has not been fully defined during the early phase of myocardial infarction (MI). In this study, we investigated the relationships between p27, vascular endothelial growth factor/hepatocyte growth factor (VEGF/HGF) and NF-κB in post-MI cardiac function repair both in vivo and in the hypoxia/ischemia-induced rat myocardiocyte model. In vivo, haplo-insufficiency of p27 improved cardiac function, diminished the infarct zone, protected myocardiocytes and increased angiogenesis by enhancing the production of VEGF/HGF. In vitro, the presence of conditioned medium from hypoxia/ischemia-induced p27 knockdown myocardiocytes reduced the injury caused by hypoxia/ischemia in myocardiocytes, and this effect was reversed by VEGF/HGF neutralizing antibodies, consistent with the cardioprotection being due to VEGF/HGF secretion. We also observed that p27 bound to IKK and that p27 haplo-insufficiency promoted IKK/p65 activation both in vivo and in vitro, thereby inducing the NF-κB downstream regulator, VEGF/HGF. Furthermore, IKKi and IKK inhibitor negated the effect of VEGF/HGF. Therefore, we conclude that p27 haplo-insufficiency protects against heart injury by VEGF/HGF mediated cardioprotection and increased angiogenesis through promoting IKK activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing / pharmacology
Cell Hypoxia
Cell Line
Culture Media, Conditioned / pharmacology
Cyclin-Dependent Kinase Inhibitor p27 / antagonists & inhibitors
Cyclin-Dependent Kinase Inhibitor p27 / genetics*
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Endothelium, Vascular / enzymology
Endothelium, Vascular / pathology
Enzyme Activation
Gene Expression Regulation
Gene Knockdown Techniques
Haploinsufficiency*
Haplotypes
Hepatocyte Growth Factor / antagonists & inhibitors
Hepatocyte Growth Factor / genetics*
Hepatocyte Growth Factor / metabolism
I-kappa B Kinase / genetics
I-kappa B Kinase / metabolism
Male
Mice
Mice, Inbred C57BL
Myocardial Infarction / enzymology
Myocardial Infarction / genetics*
Myocardial Infarction / pathology
Myocardium / metabolism*
Myocardium / pathology
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / metabolism
Myocytes, Cardiac / pathology
NF-kappa B / genetics
NF-kappa B / metabolism
Neovascularization, Physiologic*
Rats
Signal Transduction
Time Factors
Vascular Endothelial Growth Factor A / antagonists & inhibitors
Vascular Endothelial Growth Factor A / genetics*
Vascular Endothelial Growth Factor A / metabolism

Substances

Antibodies, Neutralizing
Culture Media, Conditioned
NF-kappa B
Vascular Endothelial Growth Factor A
vascular endothelial growth factor A, rat
Cyclin-Dependent Kinase Inhibitor p27
Hepatocyte Growth Factor
I-kappa B Kinase