RRC ID 67642
Author Miyazaki T, Taketomi Y, Saito Y, Hosono T, Lei XF, Kim-Kaneyama JR, Arata S, Takahashi H, Murakami M, Miyazaki A.
Title Calpastatin counteracts pathological angiogenesis by inhibiting suppressor of cytokine signaling 3 degradation in vascular endothelial cells.
Journal Circ Res
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:To specify the effect of EC calpain/CAST systems on JAK/STAT signals and their relationship with pathological angiogenesis.
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:Loss of CAST in angiogenic ECs facilitates μ-calpain-induced SOCS3 degradation, which amplifies pathological angiogenesis through interleukin-6/STAT3/VEGF-C axis.
Volume 116(7)
Pages 1170-81
Published 2015-3-27
DOI 10.1161/CIRCRESAHA.116.305363
PMID 25648699
MeSH Adenocarcinoma / blood supply Amino Acid Sequence Animals Aorta Calcium-Binding Proteins / genetics Calcium-Binding Proteins / 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* Suppressor of Cytokine Signaling Proteins / genetics Suppressor of Cytokine Signaling Proteins / physiology Vascular Endothelial Growth Factor C / antagonists & inhibitors Vascular Endothelial Growth Factor C / physiology
IF 14.467
Human and Animal Cells LLC(RCB0558)