Role of diacylglycerol induced by hypoxia in the regulation of HIF-1α activity

Temes, Elisa; Martı́n-Puig, Silvia; Aragonés, Julián; Jones, David R.; Olmos, Gemma; Mérida, Isabel; Landázuri, Manuel O.

doi:10.1016/j.bbrc.2004.01.015

Cited by 31 publications

(27 citation statements)

References 34 publications

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“…Some of these pathways were investigated in relation to HIF-1␣ regulation, which helps us to focus our further investigations. Some members of the protein kinase C family of proteins modulate HIF-1␣ transactivation function but not the protein stabilization (41) or do not interfere with HIF-1␣ function at all (42). At normoxia, in a retinal epithelial cell line, AGE had a stimulatory effect on HIF-1␣ and its DNA binding (14).…”

Section: Hif-1␣ Is Down-regulated By Hyperglycemiamentioning

confidence: 99%

Hyperglycemia Regulates Hypoxia-Inducible Factor-1α Protein Stability and Function

et al. 2004

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Hyperglycemia and hypoxia are suggested to play essential pathophysiological roles in the complications of diabetes, which may result from a defective response of the tissues to low oxygen tension. In this study, we show that in primary dermal fibroblasts and endothelial cells, hyperglycemia interferes with the function of hypoxiainducible factor-1 (HIF-1), a transcription factor that is essential for adaptive responses of the cell to hypoxia. Experiments using proteasomal and prolyl hydroxylases inhibitors indicate that hyperglycemia inhibits hypoxiainduced stabilization of HIF-1␣ protein levels against degradation and suggest that mechanisms in addition to proline hydroxylation may be involved. This effect of hyperglycemia was dose dependent and correlates with a lower transcription activation potency of HIF-1␣, as assessed by transient hypoxia-inducible reporter gene assay. Regulation of HIF-1␣ function by hyperglycemia could be mimicked by mannitol, suggesting hyperosmolarity as one critical parameter. The interference of hyperglycemia with hypoxia-dependent stabilization of HIF-1␣ protein levels was confirmed in vivo, where only very low levels of HIF-1␣ protein could be detected in diabetic wounds, as compared with chronic venous ulcers. In conclusion, our data demonstrate that hyperglycemia impairs hypoxia-dependent protection of HIF-1␣ against proteasomal degradation and suggest a mechanism by which diabetes interferes with cellular responses to hypoxia. Diabetes 53:3226 -3232, 2004 C hronic complications of diabetes are a major health problem, and it has become a priority to characterize further their pathophysiological mechanisms to develop novel, rational therapeutic strategies. Even though prolonged exposure of the tissues to hyperglycemia seems to be the primary causative factor, some other factors may play a role as far as intensive blood glucose control reduces chronic complications but does not prevent them altogether (1,2). It has become increasingly evident that hypoxia plays an important role in all diabetes complications (3). In addition to deficient blood supply as a consequence of micro-and macrovascular disease, it has been postulated that hyperglycemia induces a pseudohypoxia state. This theory is based on the finding that high glucose concentrations induce a high NADH ϩ /NAD ϩ ratio in cells even when the oxygen tension is normal (4).Adaptive responses of cells to hypoxia are mediated by the hypoxia-inducible factor-1 (HIF-1), which is a heterodimeric transcription factor composed of two subunits, HIF-1␣ and aryl hydrocarbon receptor nuclear translocator (ARNT), both constitutively expressed in mammalian cells. Regulation of HIF-1 activity is critically dependent on the degradation of the HIF-1␣ subunit in normoxia. The molecular basis of its degradation is the O 2 -dependent hydroxylation of at least one of the two proline residues (5,6) in the oxygen-dependent degradation domain of HIF-1␣ by specific prolyl 4-hydroxylases (PHDs) (7-9). In this form, HIF-1 ␣ binds to the von Hippel-Lind...

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Section: Hif-1␣ Is Down-regulated By Hyperglycemiamentioning

confidence: 99%

Hyperglycemia Regulates Hypoxia-Inducible Factor-1α Protein Stability and Function

et al. 2004

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“…In the present study, we show that R59949 is a novel activator of HIF hydroxylase activity, suggesting a possible role of PA on PHD activity. Interestingly, we found that D609, a sphingomyelin synthase/phosphatidylcholine phospholipase C inhibitor that impairs hypoxia-induced PA and HIF activation (26,38,39), also increases the formation of VHL-HIF complexes (data not shown). This accumulation of PA might play a role in regulating the interaction between VHL and HIF.…”

Section: R59949 Specifically Inhibits the Accumulation Of Hif Proteinmentioning

confidence: 92%

“…We have previously shown that hypoxia produces an increase in the levels of both diacylglycerol and phosphatidic acid (PA) through the activity of DGK (26,27). Nine DGK isoforms have so far been described, and these phosphorylate diacylglycerol to generate PA. We have found that the pharmacological inhibition of DGK activity with R59949 (28 -30) prevents the accumulation of both PA and the HIF-1␣ subunit induced by hypoxia (27).…”

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confidence: 99%

Activation of HIF-prolyl Hydroxylases by R59949, an Inhibitor of the Diacylglycerol Kinase

Temes¹,

Martı́n-Puig²,

Acosta‐Iborra³

et al. 2005

Journal of Biological Chemistry

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Hypoxia-inducible factors (HIF) are heterodimeric (␣/␤) transcription factors that play a fundamental role in cellular adaptation to low oxygen tension. In the presence of oxygen, the HIF-␣ subunit becomes hydroxylated at specific prolyl residues by prolyl hydroxylases. This post-translational modification is recognized by the von Hippel-Lindau (VHL) protein, which targets HIF-␣ for degradation. In the absence of oxygen, HIF-␣ hydroxylation is compromised and this subunit is stabilized. We have previously shown that the hypoxia-induced accumulation of HIF-␣ protein is strongly impaired by the inhibitor of diacylglycerol kinase, R59949. Here, we have investigated the mechanisms through which this inhibitor exerts its effect. We found that R59949 inhibits the accumulation of HIF-1/2␣ protein without affecting the expression of their mRNAs. We also determined that R59949 could only block the accumulation of HIF-␣ in the presence of VHL protein. In agreement with this, the binding of VHL to endogenous HIF-␣ was significantly enhanced after R59949 treatment, even under hypoxic conditions. In addition, we found that R59949 could stimulate prolyl hydroxylase both at 21% O 2 as well as at 1% O 2 . Taken together, these results reveal that R59949 is an activator of HIF prolyl hydroxylases. This is of particular interest when we consider that, to date, mainly inhibitors of these enzymes have been described.

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“…Inhibition of HIF-1a by D609 tricyclodecan-9-ylxanthogenate triggers the down regulation of VEGF, cleavage of caspase 3 as well as BNIP3 which are the causative agent for cell death in case of cerebral ischemia. The D609 inhibits the HIF-1a via inhibiting the biosynthesis of phosphatidic acid (Temes et al 2004). BNIP and BNIP3, members of Bcl2 family proteins are activated in hypoxic condition.…”

Section: Detrimental Face Of Hifmentioning

confidence: 99%