Differential Effects of Hypoxic Stress in Alveolar Epithelial Cells and Microvascular Endothelial Cells

Abstract

Under hypoxic conditions eukaryotic cells and tissues undergo adaptive responses involving glycolysis, angiogenesis, vasoconstriction and inflammation. The underlying molecular mechanisms are not yet fully elucidated and are most likely cell and tissue specific. In the lung, alveolar epithelial cells and microvascular endothelial cells are highly sensitive to hypoxia and together orchestrate a rapid and sustained adaptive response. We examined the effect of different oxygen tensions on cell viability, glucose metabolism, key transcription factors and signaling molecules, in alveolar epithelial cells (A549) and microvascular endothelial cells (HMEC-1). Both cell types tolerated hypoxia without detectable cell injury. Hypoxia induced glycolysis in both epithelial and microvascular endothelial cells, although A549 cells exhibited a higher rate of glucose consumption. The transcription factor CREB (cAMP response element binding protein) was activated with decreasing oxygen tensions in both cell types. This effect was again more marked in A549 cells, demonstrating epithelial cells to be more oxygen sensitive. Activating Transcription Factor 3 (ATF-3) was heavily induced by hypoxia in A549 cells but not in HMEC-1 cells. Both cell types exhibited hypoxia induced secretion of VEGF and IL-6. Secretion of the vasoconstrictor endothelin-1 (ET1) was increased by hypoxia in HMEC-1 cells but decreased in A549 cells. These data reveal that both cell types exhibit an adaptive response to hypoxia but alveolar epithelial cells are generally more sensitive. ET-1 was oppositely regulated by decreased oxygen tensions in the investigated cell types. The present study further elucidates the adaptive molecular mechanisms in pulmonary hypoxia and demonstrates cell specific responses.

Endothelin-converting enzyme is a plausible target gene for hypoxia-inducible factor

“…Hypoxia has long been recognized to stimulate ET expression, [6][7][8] and more recently hypoxia-inducible transcription factors (HIFs) have been defined as potent stimuli for induction of the pro-hormone. 6,[9][10][11][12] However, we have recently reported that renal ECE-1 expression is markedly enhanced in diabetic rat kidneys and following the administration of iodinated contrast agents, 13 conditions characterized by elevated plasma and renal ET 14,15 and intensified renal parenchymal hypoxia and HIF expression.…”

Isoflurane Preconditioning Increases Survival of Rat Skin Random-Pattern Flaps by Induction of HIF-1a Expression

“…Thus, in this study, we extend the previous findings by showing a similar protective effect in the skin flap tissues. Vascular endothelial cells are the lining component for all vascular networks, and are sensitive to ischemia [27,28]. HUVECs are regarded as a standard endothelial cell line for analysis of vasoreactive responses to various conditions [8,28].…”

SEURAT-1 liver gold reference compounds: a mechanism-based review

“…Under normal oxygen conditions, proline hydroxylation reactions target HIF-1α for proteasomal degradation (Signorelli et al 2010). This reaction requires oxygen so that under low oxygen tensions, degradation is inhibited, and HIF-1 accumulates, translocates to the nucleus, heterodimerizes with ARNT (aka HIF-1α), and commences the transcription of genes through specific hypoxia responsive elements (HRE) (Semenza 2001;Signorelli et al 2010).…”

“…Under normal oxygen conditions, proline hydroxylation reactions target HIF-1α for proteasomal degradation (Signorelli et al 2010). This reaction requires oxygen so that under low oxygen tensions, degradation is inhibited, and HIF-1 accumulates, translocates to the nucleus, heterodimerizes with ARNT (aka HIF-1α), and commences the transcription of genes through specific hypoxia responsive elements (HRE) (Semenza 2001;Signorelli et al 2010). Such genes include those involved in erythropoiesis (e.g., erythropoietin (EPO)), glycolysis [hexokinase 2 (HK2), phosphoglycerate kinase 1 (PGK1), lactate dehydrogenase (LDHA), and glucose transporter 1 (SLC2A1)], and in angiogenesis (vascular endothelial growth factor (VEGFA), endothelin 1 (ET1)) (Hu et al 2003;Schodel et al 2011;Semenza and Wang 1992).…”