Placenta Growth Factor-induced Early Growth Response 1 (Egr-1) Regulates Hypoxia-inducible Factor-1α (HIF-1α) in Endothelial Cells

Abstract

Leukotrienes, the lipid inflammatory products derived from arachidonic acid, are involved in the pathogenesis of respiratory and cardiovascular diseases and reactive airway disease in sickle cell disease. Placenta growth factor (PlGF), elaborated from erythroid cells, increased the mRNA expression of 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) in human pulmonary microvascular endothelial cells. PlGF-induced both promoter activity and mRNA expression of hypoxia-inducible factor-1␣ (HIF-1␣), which was abrogated by early growth response-1 (EGR-1) small interfering RNA. PlGF showed a temporal reciprocal relationship in the mRNA levels of EGR-1 and NAB2, the latter a repressor of Egr-1. Moreover, Nab2, but not mutant Nab2, significantly reduced promoter activity and mRNA expression of HIF-1␣ and also reduced expression of the HIF-1␣ target gene FLAP. Furthermore, overexpression of Egr-1 led to increased promoter activities for both HIF-1␣ and FLAP in the absence of PlGF. Additionally, the Egr-1-mediated induction of HIF-1␣ and FLAP promoters was reduced to basal levels by EGR-1 small interfering RNA. The binding of Egr-1 to HIF-1␣ promoter was corroborated by electrophoretic mobility shift assay and chromatin immunoprecipitation assay, which showed increased Egr-1 binding to the HIF-1␣ promoter in response to PlGF stimulation. These studies provide a novel mechanism for PlGF-mediated regulation of HIF-1␣ via Egr-1, which results in increased FLAP expression. This study provides a new therapeutic target, namely Egr-1, for attenuation of elevated leukotriene levels in patients with sickle cell disease and other inflammatory diseases.

Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Krüppel-like factor

“…Previously published results demonstrate clearly that PlGF is expressed highly in patients with SCD 21,38,39 and stimulates production of the potent vasoconstrictor ET-1 and other factors, [40][41][42][43][44][45][46] which is then associated in adults with SCD with echocardiographic indicators of elevated pulmonary artery pressure and in mice with histological evidence of pulmonary hypertension. 21,41 These prior results combined with our current data indicate for the first time a linkage between iron and expression of EKLF, PlGF, and ET-1 and clinical elevation of pulmonary artery pressure in humans with SCD with increased mortality.…”

Pseudomonas aeruginosa Alkyl Quinolones Repress Hypoxia-Inducible Factor 1 (HIF-1) Signaling through HIF-1α Degradation

“…aeruginosa cell-free culture supernatants downregulate HIF-1␣ protein levels in a psqA-dependent manner. To further investigate this novel observation, we targeted the 2-alkyl-4-quinolone (AQ) signaling pathway since the production of extracellular factors by P. aeruginosa is significantly dependent on this intercellular signaling system and AQ signal molecules have been recently shown to modulate the expression of two regulators of the HIF-1 pathway (23,24), NF-B (43, 52) and early growth factor 1 (EGR1) (37,51). Therefore, IB3-1 cells were incubated with culture supernatants from a P. aeruginosa PA14 wt strain, an isogenic pqsA mutant strain impaired in AQ production (PA14 pqsA) (10), and an isogenic pqsL mutant strain (PA14 pqsL), known to produce all AQs and to overproduce the principal AQ signal molecule, PQS (8).…”

Angiotensin-(1–1) Suppresses Hepatocellular Carcinoma Growth and Angiogenesis via Complex Interactions of Angiotensin II Type 1 Receptor, Angiotensin II Type 2 Receptor and Mas Receptor

“…Ang-(1-7) has been confirmed to reduce the expression of the HIF-1α gene (47), which suggests that HIF-1α may be a key mediator of Ang-(1-7) in regulating angiogenesis. Ang-(1-7) causes reduced PIGF level (44), which may also provide feedback to regulate HIF-1α expression and function (48). The angiogenic and tumor-promoting activity of PIGF remains controversial (49,50).…”