Abstract
Plasminogen Kringle 5(K5) is a proteolytic fragment of plasminogen, which displays potent anti-angiogenic activities. K5 has been shown to induce apoptosis in proliferating endothelial cells; however the exact mechanism has not been well explored. The present study was designed to elucidate the possible molecular mechanism of K5-induced endothelial cell apoptosis. Our results showed that K5 inhibited basic fibroblast growth factors activated in human umbilical vein endothelial cells (HUVECs), indicating proliferation in a dose-dependent manner and induced endothelial cell death via apoptosis. K5 exposure activated caspase 7, 8 and 9. These results suggested that both the intrinsic mitochondrial apoptosis pathway and extrinsic pathway might be involved in K5-induced apoptosis. K5 reduced mitochondrial membrane potential (MMP) of HUVECs, demonstrating mitochondrial depolarization in HUVECs. K5 increased the ratio of Bak to Bcl-xL on mitochondria, decreased the ratio in cytosol, and had no effect on the total amounts of these proteins. K5 also did not effect on Bax/Bcl-2 distribution. K5 increased the ratio of Bak to Bcl-xL on mitochondrial that resulted in mitochondrial depolarization, cytochrome c release and consequently the cleavage of caspase 9. These results suggested that K5 induces endothelial cell apoptosis at least in part via activating mitochondrial apoptosis pathway. The regulation of K5 on Bak and Bcl-xL distribution may play an important role in endothelial cell apoptosis. These results provide further insight into the anti-angiogenesis roles of K5 in angiogenesis-related ocular diseases and solid tumors.
Original language | English (US) |
---|---|
Pages (from-to) | 846-855 |
Number of pages | 10 |
Journal | Apoptosis |
Volume | 16 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2011 |
Funding
Acknowledgments This study was supported by National Nature Science Foundation of China, Grant Number: 30600724, 30700120, 30872980, 30971208, 30973449, 81070746, 81001014; National Key Sci-Tech Special Project of China, Grant Number: 2008ZX10002-019, 2009ZX09103-642; Key Project of Nature Science Foundation of Guangdong Province, China, Grant Number: 10251008901000009; Guangdong natural science fund, Grant Number: 7002329, 10151008901000007; Program for Young Teacher in University, Grant Number: 09YKPY73, 10YKPY28; Department of health of Guangdong Province medical research fund, Grant Number A2008548; Program for Bureau of Health of Guangzhou Municipality fund, Grant Number: 2007-YB-061.
Keywords
- Apoptosis
- Bak
- Bcl-2 family
- Bcl-x
- Cytochrome c
- Endothelial cell
- Kringle 5
- Mitochondrial membrane potential
ASJC Scopus subject areas
- Pharmacology
- Pharmaceutical Science
- Clinical Biochemistry
- Cell Biology
- Biochemistry, medical
- Cancer Research