The Expression of VHL (Von Hippel-Lindau) After Traumatic Spinal Cord Injury and Its Role in Neuronal Apoptosis

Abstract

The VHL (Von Hippel-Lindau) gene is a tumor suppressor gene, which is best known as an E3 ubiquitin ligase that negatively regulates the hypoxia inducible factor. The inactivation of VHL gene could result in the abnormal synthesis of VHL protein, which is in contact with the development and occurrence of renal clear cell carcinoma. However, the expression and possible function of VHL in central nervous system (CNS) is still unclear. To examine the function of VHL in CNS injury and repair, we used an acute spinal cord injury (SCI) model in adult rats. Western blot analysis showed an important upregulation of VHL protein, reaching a peak at day 3 and then declined during the following days. Double immunofluorescence staining showed that VHL was co-expressed with neurons, but not with astrocytes and microglia. Moreover, we detected that active caspase-3 had co-localized with VHL in neurons after SCI. Additionally in vitro, VHL depletion, by short interfering RNA, significantly reduced neuronal apoptosis. In conclusion, these data suggested that the change of VHL protein expression was related to neuronal apoptosis after SCI.

Neuroprotective effects respond to cerebral ischemia without susceptibility to HB‐tumorigenesis in VHL heterozygous knockout mice

“…This was supported by our study that the number of Caspase‐3+ neural cells was decreased in the ischemic boundary zone of heterozygous VHL mice after MCAO. Moreover, the survival effect of VHL deletion was also confirmed in mice with spinal cord injury, in which VHL was co‐localized with caspase‐3 in neurons, and neuronal apoptosis was significantly reduced by VHL depletion through short interfering RNA . We also found increased GFAP+ neural cells in heterozygous VHL mice.…”

“…Moreover, the survival effect of VHL deletion was also confirmed in mice with spinal cord injury, in which VHL was co-localized with caspase-3 in neurons, and neuronal apoptosis was significantly reduced by VHL depletion through short interfering RNA. 44 We also found increased GFAP+ neural cells in heterozygous VHL mice. The enhanced GFAP+ cells were found to activate astrocytes, reduce neuronal death following brain ischemia, 45 and were associated with neuroprotective agent 2-oxoglutarate and Ilexonin A, 46,47 indicating that neuronal regeneration might be enhanced in heterozygous VHL mice.…”

Considerations about Hypoxic Changes in Neuraxis Tissue Injuries and Recovery

“…Under normal oxygenation, the HIF-1α protein subunit is rapidly degraded by proteosomes. The whole process is mediated by the Von Hipple-Lindau protein factor (pVHL), an E3 ubiquitin recognition and binding component that promotes ubiquitin-dependent proteolysis of this subunit [ 31 ]. Under hypoxic conditions, the degradation of the HIF-1α subunit is suppressed, leading to gene transcription activation.…”

“…The increase of VHL protein was associated with neuronal apoptosis because it was not found in astrocytes and microglia. Decreased VHL levels may reduce glutamate-dependent neuronal apoptosis, but increased expression of VHL protein above a critical limit does not appear to produce further changes in neuronal apoptosis [ 31 ].…”

Proteases and Their Modulators in Cancer Therapy: Challenges and Opportunities

“…VHL is a tumor suppressor, and its major substrate is hypoxia inducible factor-1α (HIF-1α). 72 In 2012, PROTAC 15 was developed as a drug against the interaction between VHL and HIF1α (Figure 9). 61 The VHL ligand (Figure 7) could be coupled to the recognition site of HIF1α in VHL.…”