Expression of Hypoxia Inducible Factor 1alpha Is Protein Kinase A-dependent in Primary Cortical Astrocytes Exposed to Severe Hypoxia

Abstract

The hypoxia inducible factor 1 (HIF-1) and the cyclic AMP-responsive element binding protein (CREB) are two transcription factors that have been studied in the context of neuronal survival and neurodegeneration. HIF-1 upregulation and CREB activation have been observed not only in neurons but also in astrocytes under conditions of hypoxia. We hypothesized that activation of CREB regulate HIF-1α expression in the nucleus of cortical astrocytes under in vitro ischemic condition. To test the hypothesis, we determined the effects of inhibiting the CREB activation pathway on the expression of HIF-1α protein in astrocytes exposed to CoCl and severe hypoxia (near anoxia, 0.1% O). The results demonstrated that inhibition of CaMKII and CaMKIV had no effect on both HIF-1α and pCREB expression in cortical astrocytes exposed to CoCl and anoxia. In contrast, PKA inhibition lowered the expression of HIF-1α and pCREB expression. Furthermore, the inhibition of PKA but not CaMKII or CaMKIV increased cell death of astrocytes exposed to near anoxia. The results suggest that PKA plays an important role in the cell survival signaling pathways in astrocytes.

Serum Hypoxia-Inducible Factor 1alpha Levels Correlate with Outcomes After Intracerebral Hemorrhage

“…The patients were admitted at a median value of 6.5 h after symptom onset (range, 0.5-24.0 h; 25th−75th percentiles, 4.0-9.0 h), with their blood samples collected from 1.0 to 26.0 h (median, 9.0 h; 25th−75th percentiles, 6.0-13.0 h) after stroke. As regards hemorrhagic clinical severity, the median value of GCS scores was 13 (range, 4-15; 25th−75th percentiles, [9][10][11][12][13][14][15]. With respect to some radiological parameters, hematomas of 20 cases were located at cerebral lobe; those of 15 cases were found at infratentorial cavity; intraventricular bleedings was present in 26 cases; and the median value of hematoma volume was 14.5 mL (25th−75th percentiles, 6.7-30 mL; range, 2.0-64.8 mL).…”

“…However, HIF-1α, acting as a transcription factor, is located in intracellular compartment. 8,9 Thus, it is speculated that the Figure 3 Relationship between serum hypoxia-inducible factor 1alpha levels and hematoma volume after intracerebral hemorrhage. When hematoma volume was a continuous variable, serum hypoxia-inducible factor 1alpha levels were significantly raised with rising hematoma volume using Spearman correlation coefficients (P<0.001).…”

Regulation of Gene Expression under Hypoxic Conditions

“…The hypoxic response is important for survival of both neurons and astrocytes in ischemic diseases. HIF-1 and CREB are activated in astrocytes upon hypoxic treatment, and PKA plays a key role in the activation of both molecules [53]. CREB also functions in iron metabolism by regulating IRP1 [54].…”

The Role of Astrocytes in the Central Nervous System Focused on BK Channel and Heme Oxygenase Metabolites: A Review

“…Activation of HIF-1α under ischemic conditions has been shown to protect astrocytes against oxidative stress. In cultured rat astrocytes, HIF-1α has a protective role by promoting astrocyte survival after excitotoxic and hypoxic injury [88,89]. A HIF-1α downstream factor, VEGF, also has protective effects against ischemic injury by stimulating angiogenesis, mitochondria biogenesis, neuronal survival, and neurogenesis [90,91,92,93].…”