Expression of Hypoxia-Inducible Factor (HIF)-1a-Vascular Endothelial Growth Factor (VEGF)-Inhibitory Growth Factor (ING)-4- axis in sarcoidosis patients

Abstract

BackgroundSarcoidosis is a granulomatous disorder of unknown etiology. The term of immunoangiostasis has been addressed by various studies as potentially involved in the disease pathogenesis. The aim of the study was to investigate the expression of the master regulator of angiogenesis hypoxia inducible factor (HIF)-1a – vascular endothelial growth factor (VEGF)- inhibitor of growth factor 4-(ING4) - axis within sarcoid granuloma.MethodsA total of 37 patients with sarcoidosis stages II-III were recruited in our study. Tissue microarray technology coupled with immunohistochemistry analysis were applied to video-assisted thoracoscopic surgery (VATS) lung biopsy samples collected from 37 sarcoidosis patients and 24 controls underwent surgery for benign lesions of the lung. Computerized image analysis was used to quantify immunohistochemistry results. qRT-PCR was used to assess HIF-1a and ING4 expression in 10 sarcoidosis mediastinal lymph node and 10 control lung samples.ResultsHIF-1a and VEGF-ING4 expression, both in protein and mRNA level, was found to be downregulated and upregulated, respectively, in sarcoidosis samples compared to controls. Immunohistochemistry coupled with computerized image analysis revealed minimal expression of HIF-1a within sarcoid granulomas whereas an abundant staining of ING4 and VEGF in epithelioid cells was also visualized.ConclusionsOur data suggest an impairment of the HIF-1a – VEGF axis, potentialy arising by ING4 overexpression and ultimately resulting in angiostasis and monocyte recruitment within granulomas. The concept of immunoangiostasis as a possible protection mechanism against antigens of infectious origin needs further research to be verified.

Noncommunicable Diseases

“…Our results are partly in accord with the observations (Tzouvelekis et al 2012;Antoniou et al 2006;Déry et al 2005). The known mechanism of inhibitory properties of ING-4 is based on the interaction with HIF prolyl hydroxylases and NF-κB subunit -ReIA.…”

“…Under hypoxic conditions, HIF-1 upregulation may induce alveolar cell apoptosis and epithelial-mesenchymal transmission (EMT), thus potentially contributing to pulmonary fibrosis (Kim et al 2006). VEGF, by controlling monocyte recruitment, may be involved in granuloma formation (Tzouvelekis et al 2012;Tolnay et al 1998). In chronic experimental hypoxia, leading to acute lung fibrosis, inflammation, fibrosis, and pulmonary hypertension, the increased HIF-1A protein and its DNA binding activity have been observed in pulmonary epithelial cells (Shimoda and Semenza 2011;Yu et al 1998).…”

Regulation of the hypoxic tumor environment in hepatocellular carcinoma using RNA interference

“…Additionally, hypoxia induced by medical or surgical treatment induces the accumulation of HIF-1α inside tumor cells and its subsequent migration into the nuclei, where it promotes the expression of angiogenesis-related genes and increases oxygen supply to the tumor [57]. It also induces the expression of metastasis-related genes [12, 17, 31]. These hypoxia-induced processes reduce cellular injury and enable continuous tumor growth by ensuring an effective supply of oxygen to the tumor [31].…”

“…The key factor involved in this process is IL-8, which is up-regulated by hypoxic conditions during tumor proliferation [12, 56, 58]. IL-8 induces angiogenesis by activating vascular endothelial cells [59].…”

“…Active HIF consists of an alpha subunit and a beta subunit [2, 11, 12]. Three alpha subunits, termed HIF1a, HIF2a, and HIF3a, have been described in humans, mice, and rats; all bind to a common b subunit named, alternatively, HIF1b, or the aryl-hydrocarbon-nuclear receptor translocator (ARNT) [13, 14].…”