Abstract | RATIONALE:
Janus kinase/signal transducer and activator of transcription (JAK/STAT) signals and their endogenous inhibitor, suppressor of cytokine signaling 3 (SOCS3), in vascular endothelial cells (ECs) reportedly dominate the pathological angiogenesis. However, how these inflammatory signals are potentiated during pathological angiogenesis has not been fully elucidated. We suspected that an intracellular protease calpain, which composes the multifunctional proteolytic systems together with its endogenous inhibitor calpastatin (CAST), contributes to the JAK/STAT regulations. OBJECTIVE: METHODS AND RESULTS: The loss of CAST, which is ensured by several growth factor classes, was detectable in neovessels in murine allograft tumors, some human malignant tissues, and oxygen-induced retinopathy lesions in mice. EC-specific transgenic introduction of CAST caused downregulation of JAK/STAT signals, upregulation of SOCS3 expression, and depletion of vascular endothelial growth factor ( VEGF)-C, thereby counteracting unstable pathological neovessels and disease progression in tumors and oxygen-induced retinopathy lesions in mice. Neutralizing antibody against VEGF-C ameliorated pathological angiogenesis in oxygen-induced retinopathy lesions. Small interfering RNA-based silencing of endogenous CAST in cultured ECs facilitated μ- calpain-induced proteolytic degradation of SOCS3, leading to VEGF-C production through amplified interleukin-6-driven STAT3 signals. Interleukin-6-induced angiogenic tube formation in cultured ECs was accelerated by CAST silencing, which is suppressible by pharmacological inhibition of JAK/STAT signals, antibody-based blockage of VEGF-C, and transfection of calpain-resistant SOCS3, whereas transfection of wild-type SOCS3 exhibited modest angiostatic effects. CONCLUSIONS:
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Authors | Takuro Miyazaki, Yoshitaka Taketomi, Yuta Saito, Tomohiko Hosono, Xiao-Feng Lei, Joo-Ri Kim-Kaneyama, Satoru Arata, Haruo Takahashi, Makoto Murakami, Akira Miyazaki |
Journal | Circulation research
(Circ Res)
Vol. 116
Issue 7
Pg. 1170-81
(Mar 27 2015)
ISSN: 1524-4571 [Electronic] United States |
PMID | 25648699
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2015 American Heart Association, Inc. |
Chemical References |
- Calcium-Binding Proteins
- Cytokines
- Recombinant Fusion Proteins
- SOCS3 protein, human
- STAT Transcription Factors
- Socs3 protein, mouse
- Suppressor of Cytokine Signaling 3 Protein
- Suppressor of Cytokine Signaling Proteins
- Vascular Endothelial Growth Factor C
- vascular endothelial growth factor C, mouse
- calpastatin
- Janus Kinases
- Calpain
- mu-calpain
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Topics |
- Adenocarcinoma
(blood supply)
- Amino Acid Sequence
- Animals
- Aorta
- Calcium-Binding Proteins
(genetics, physiology)
- Calpain
(metabolism)
- Carcinoma, Lewis Lung
(blood supply)
- Cells, Cultured
- Cytokines
(physiology)
- Endothelial Cells
(metabolism)
- Female
- Glioblastoma
(blood supply)
- Humans
- Janus Kinases
(physiology)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Molecular Sequence Data
- Mutagenesis, Site-Directed
- Neoplasms
(blood supply)
- Neovascularization, Pathologic
(physiopathology)
- Recombinant Fusion Proteins
(metabolism)
- Retinopathy of Prematurity
(physiopathology)
- STAT Transcription Factors
(physiology)
- Signal Transduction
(physiology)
- Suppressor of Cytokine Signaling 3 Protein
- Suppressor of Cytokine Signaling Proteins
(antagonists & inhibitors, genetics, physiology)
- Vascular Endothelial Growth Factor C
(antagonists & inhibitors, physiology)
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