title: Plasminogen K5 activates mitochondrial apoptosis pathway in endothelial cells by regulating Bak and Bcl-x(L) subcellular distribution.
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-x(L) 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-x(L) 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-x(L) 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.
authors.affiliation: Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
authors.forename: Xiaoqiong
authors.initials: X
authors.lastname: Gu
authors.forename: Yachao
authors.initials: Y
authors.lastname: Yao
authors.forename: Rui
authors.initials: R
authors.lastname: Cheng
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Dai
authors.forename: Genping
authors.initials: G
authors.lastname: Wan
authors.forename: Zhonghan
authors.initials: Z
authors.lastname: Yang
authors.forename: Weibin
authors.initials: W
authors.lastname: Cai
authors.forename: Guoquan
authors.initials: G
authors.lastname: Gao
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology* / Q000502:physiology; D010958:Plasminogen / Q000494:pharmacology* / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects; D014471:Umbilical Veins / Q000166:cytology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; D010446:Peptide Fragments; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C491499:plasminogen kringle 5; D016222:Fibroblast Growth Factor 2; D010958:Plasminogen; D045304:Cytochromes c