Inositol polyphosphate multikinase inhibits angiogenesis via inositol pentakisphosphate-induced HIF-1α degradation

Chenglai Fu, Richa Tyagi, Alfred C. Chin, Tomas Rojas, Ruo Jing Li, Prasun Guha, Isaac A. Bernstein, Feng Rao, Risheng Xu, Jiyoung Cha, Jing Xu, Adele M Snowman, Gregg L Semenza, Solomon H Snyder

Research output: Contribution to journalArticle

Abstract

Rationale: Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored. Objective: We have investigated the role of IPMK in regulating angiogenesis. Methods and Results: Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of VEGF (vascular endothelial growth factor), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. HIF (hypoxia-inducible factor)-1α is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF-1α protein and thus VEGF. HIF-1α is constitutively ubiquitinated by pVHL (von Hippel-Lindau protein) followed by proteasomal degradation under normal conditions. However, HIF-1α is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells. IP5 reinstates the interaction of HIF-1α and pVHL. HIF-1α prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK-deleted cells. IP5 promotes HIF-1α prolyl hydroxylation and thus pVHL-dependent degradation of HIF- 1α. Deletion of IPMK in mouse brain increases HIF-1α/VEGF levels and vascularization. The increased VEGF in IPMK KO disrupts blood-brain barrier and enhances brain blood vessel permeability. Conclusions: IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1α hydroxylation and thus pVHL-dependent degradation of HIF-1α.

Original languageEnglish (US)
Pages (from-to)457-472
Number of pages16
JournalCirculation Research
Volume122
Issue number3
DOIs
StatePublished - Feb 2 2018

Fingerprint

Hypoxia-Inducible Factor 1
Vascular Endothelial Growth Factor A
Hydroxylation
inositol polyphosphate multikinase
inositol pentaphosphate
Blood Vessels
Brain Hypoxia
Blood-Brain Barrier

Keywords

  • Blood-brain barrier
  • Egln1 protein
  • Hydroxylation
  • Inositol phosphates
  • Vascular endothelial growth factor A
  • Von Hippel-Lindau protein

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Inositol polyphosphate multikinase inhibits angiogenesis via inositol pentakisphosphate-induced HIF-1α degradation. / Fu, Chenglai; Tyagi, Richa; Chin, Alfred C.; Rojas, Tomas; Li, Ruo Jing; Guha, Prasun; Bernstein, Isaac A.; Rao, Feng; Xu, Risheng; Cha, Jiyoung; Xu, Jing; Snowman, Adele M; Semenza, Gregg L; Snyder, Solomon H.

In: Circulation Research, Vol. 122, No. 3, 02.02.2018, p. 457-472.

Research output: Contribution to journalArticle

Fu, Chenglai ; Tyagi, Richa ; Chin, Alfred C. ; Rojas, Tomas ; Li, Ruo Jing ; Guha, Prasun ; Bernstein, Isaac A. ; Rao, Feng ; Xu, Risheng ; Cha, Jiyoung ; Xu, Jing ; Snowman, Adele M ; Semenza, Gregg L ; Snyder, Solomon H. / Inositol polyphosphate multikinase inhibits angiogenesis via inositol pentakisphosphate-induced HIF-1α degradation. In: Circulation Research. 2018 ; Vol. 122, No. 3. pp. 457-472.
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abstract = "Rationale: Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored. Objective: We have investigated the role of IPMK in regulating angiogenesis. Methods and Results: Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of VEGF (vascular endothelial growth factor), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. HIF (hypoxia-inducible factor)-1α is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF-1α protein and thus VEGF. HIF-1α is constitutively ubiquitinated by pVHL (von Hippel-Lindau protein) followed by proteasomal degradation under normal conditions. However, HIF-1α is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells. IP5 reinstates the interaction of HIF-1α and pVHL. HIF-1α prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK-deleted cells. IP5 promotes HIF-1α prolyl hydroxylation and thus pVHL-dependent degradation of HIF- 1α. Deletion of IPMK in mouse brain increases HIF-1α/VEGF levels and vascularization. The increased VEGF in IPMK KO disrupts blood-brain barrier and enhances brain blood vessel permeability. Conclusions: IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1α hydroxylation and thus pVHL-dependent degradation of HIF-1α.",
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T1 - Inositol polyphosphate multikinase inhibits angiogenesis via inositol pentakisphosphate-induced HIF-1α degradation

AU - Fu, Chenglai

AU - Tyagi, Richa

AU - Chin, Alfred C.

AU - Rojas, Tomas

AU - Li, Ruo Jing

AU - Guha, Prasun

AU - Bernstein, Isaac A.

AU - Rao, Feng

AU - Xu, Risheng

AU - Cha, Jiyoung

AU - Xu, Jing

AU - Snowman, Adele M

AU - Semenza, Gregg L

AU - Snyder, Solomon H

PY - 2018/2/2

Y1 - 2018/2/2

N2 - Rationale: Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored. Objective: We have investigated the role of IPMK in regulating angiogenesis. Methods and Results: Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of VEGF (vascular endothelial growth factor), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. HIF (hypoxia-inducible factor)-1α is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF-1α protein and thus VEGF. HIF-1α is constitutively ubiquitinated by pVHL (von Hippel-Lindau protein) followed by proteasomal degradation under normal conditions. However, HIF-1α is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells. IP5 reinstates the interaction of HIF-1α and pVHL. HIF-1α prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK-deleted cells. IP5 promotes HIF-1α prolyl hydroxylation and thus pVHL-dependent degradation of HIF- 1α. Deletion of IPMK in mouse brain increases HIF-1α/VEGF levels and vascularization. The increased VEGF in IPMK KO disrupts blood-brain barrier and enhances brain blood vessel permeability. Conclusions: IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1α hydroxylation and thus pVHL-dependent degradation of HIF-1α.

AB - Rationale: Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored. Objective: We have investigated the role of IPMK in regulating angiogenesis. Methods and Results: Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of VEGF (vascular endothelial growth factor), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. HIF (hypoxia-inducible factor)-1α is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF-1α protein and thus VEGF. HIF-1α is constitutively ubiquitinated by pVHL (von Hippel-Lindau protein) followed by proteasomal degradation under normal conditions. However, HIF-1α is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells. IP5 reinstates the interaction of HIF-1α and pVHL. HIF-1α prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK-deleted cells. IP5 promotes HIF-1α prolyl hydroxylation and thus pVHL-dependent degradation of HIF- 1α. Deletion of IPMK in mouse brain increases HIF-1α/VEGF levels and vascularization. The increased VEGF in IPMK KO disrupts blood-brain barrier and enhances brain blood vessel permeability. Conclusions: IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1α hydroxylation and thus pVHL-dependent degradation of HIF-1α.

KW - Blood-brain barrier

KW - Egln1 protein

KW - Hydroxylation

KW - Inositol phosphates

KW - Vascular endothelial growth factor A

KW - Von Hippel-Lindau protein

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