PICK1 modulates glycolysis and angiogenesis of hypoxic endothelial cells by regulating iron homeostasis

Iron accumulation, which is controlled by transferrin receptor 1 (TfR1), modulates hypoxia-inducible factor-1α (HIF-1α) activation and angiogenesis of hypoxic endothelial cells. The study examined the role of protein interacting with C-kinase 1 (PICK1), a scaffold protein containing PDZ domain, in r...

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Published in:Molecular and cellular biochemistry 2024-05, Vol.479 (5), p.1297-1312
Main Authors: Cao, Yu, Wang, Hongbo, Hu, Shuyu, Xu, Qiaomin, Ma, Jun, Wang, Huile, Xiong, Xiangqing, Wang, Wantie, Wang, Liangrong
Format: Article
Language:English
Subjects:
6-Phosphofructo-2-kinase
Accumulation
Angiogenesis
Antigens, CD - genetics
Antigens, CD - metabolism
Biochemistry
Biomedical and Life Sciences
Cancer Research
Cardiology
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Hypoxia
Cell proliferation
Deferoxamine
Endothelial cells
Glycolysis
Growth factors
Homeostasis
Human Umbilical Vein Endothelial Cells - metabolism
Humans
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Hypoxia-inducible factor 1a
Iron
Iron - metabolism
Kinases
Life Sciences
Medical Biochemistry
Neovascularization, Physiologic
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Phosphofructokinase
Proteins
Receptors, Transferrin - metabolism
siRNA
Transferrin
Umbilical vein
Up-regulation
Vascular endothelial growth factor
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Summary:Iron accumulation, which is controlled by transferrin receptor 1 (TfR1), modulates hypoxia-inducible factor-1α (HIF-1α) activation and angiogenesis of hypoxic endothelial cells. The study examined the role of protein interacting with C-kinase 1 (PICK1), a scaffold protein containing PDZ domain, in regulating glycolysis and angiogenesis of hypoxic vascular endothelial cells through its potential effect on TfR1, which features a supersecondary structure that interacts with the PDZ domain. Iron chelator deferoxamine and TfR1 siRNA were employed to assess the impact of iron accumulation on angiogenesis, while the effects of PICK1 siRNA and overexpressing lentivirus on TfR1-mediated iron accumulation were also investigated in hypoxic human umbilical vein vascular endothelial cells (HUVECs). The study found that 72-h hypoxia impaired the proliferation, migration, and tube formation of HUVECs, and reduced the upregulation of vascular endothelial growth factor, HIF-1α, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, and PICK1, while increasing the expression of TfR1 as compared to 24-h hypoxia. Administration of deferoxamine or TfR1 siRNA reversed these effects and led to increased glycolysis, ATP content, and phosphofructokinase activity, along with increased PICK1 expression. PICK1 overexpression improved glycolysis, enhanced angiogenic capacity, and attenuated TfR1 protein upregulation in hypoxic HUVECs, with higher expression of angiogenic markers, which could be significantly reversed by the PDZ domain inhibitor. PICK1 knockdown exerted opposite effects. The study concluded that PICK1 modulated intracellular iron homeostasis, thereby promoting glycolysis and angiogenesis of HUVECs in response to prolonged hypoxia, at least in part, by regulating TfR1 expression.
ISSN:0300-8177
1573-4919
DOI:10.1007/s11010-023-04795-z