Expression of HIF-1A/VEGF/ING-4 Axis in Pulmonary Sarcoidosis

Abstract

Angiogenesis/angiostasis regulated by hypoxia inducible factor-1A (HIF-1A)/vascular endothelial growth factor (VEGF)/inhibitor of growth protein 4 (ING-4) axis may be crucial for the course and outcome of sarcoidosis. Overexpression of angiogenic factors (activation of VEGF through HIF-1A) may predispose to chronic course and lung fibrosis, whereas immunoangiostasis (related to an overexpression of inhibitory ING-4) may be involved in granuloma formation in early sarcoid inflammation, or sustained or recurrent formation of granulomas. In this work we investigated gene expression of HIF-1A, VEGF and ING-4 in bronchoalveolar fluid (BALF) cells and in peripheral blood (PB) lymphocytes of sarcoidosis patients (n=94), to better understand mechanisms of the disease and to search for its biomarkers. The relative gene expression level (RQ value) was analyzed by qPCR. The results were evaluated according to the presence of lung parenchymal involvement (radiological stage I vs. II-IV), acute vs. insidious onset, lung function tests, calcium metabolism parameters, percentage of lymphocytes (BALL%) and BAL CD4+/CD8+ in BALF, age, and gender. In BALF cells, the ING-4 and VEGF RQ values were increased, while HIF-1A expression was decreased. In PB lymphocytes all studied genes were overexpressed. Higher expression of HIF-1A in PB lymphocytes of patients with abnormal spirometry, and in BALF cells of patients with lung volume restriction was found. VEGF gene expression in BALF cells was also higher in patients with abnormal spirometry. These findings were in line with previous data on the role of HIF-1A/VEGF/ING-4 axis in the pathogenesis of sarcoidosis. Up-regulated HIF-1A and VEGF genes are linked to acknowledged negative prognostics.

Altered miRNA expression in pulmonary sarcoidosis

“…Our earlier study assesses the expression of genes involved in these two pathways, i.e. the regulation of fibrosis and angiogenetic/angiostatic homeostasis, in patients with sarcoidosis [ 6 , 34 ]. Our findings reveal statistically significant correlations between the expression of some of the studied miRNAs and the expression of genes which had been studied earlier [ 6 , 34 ].…”

Selected Molecular Events in the Pathogenesis of Sarcoidosis—Recent Advances

“…In contrary, up-regulation on transcriptional level of proangiogenic factors such as HIF-1A and VEGF genes in PB lymphocytes of sarcoidosis patients has been documented [103]. Moreover the negative correlation between expression level of mRNA HIF-1A and lung function test results (FEV 1 /FVC) in sarcoidosis patients with parenchymal involvement has been documented [103]. This is an important observation due to the fact that observed up-regulation of HIF-1A may inhibit the epithelial cell repair and therefore may render the epithelial lung injury towards pulmonary fibrosis in sarcoidosis patients.…”

“…The combination of the downregulation of HIF-1A within sarcoid granulomas with VEGF and ING-4 up-regulation may be the cause of the angiostatic environment found within granulomas, as well as the macrophage chemotaxis within sarcoid lesions [99]. In contrary, up-regulation on transcriptional level of proangiogenic factors such as HIF-1A and VEGF genes in PB lymphocytes of sarcoidosis patients has been documented [103]. Moreover the negative correlation between expression level of mRNA HIF-1A and lung function test results (FEV 1 /FVC) in sarcoidosis patients with parenchymal involvement has been documented [103].…”

Exploring the dynamic changes between pulmonary and cutaneous sarcoidosis based on gene expression

“…Unsupervised bioinformatics analyses of gene expression data can identify highly regulated molecular pathways that are likely to promote abnormal granulomatous inflammation. Up-regulated hypoxia inducible factor-1A (HIF-1A) and vascular endothelial growth factor (VEGF) genes have been linked to acknowledged negative prognostics [22]. In this study, we utilized the gene expression profiles of different staged cutaneous sarcoidosis (shorten as CSC) and pulmonary sarcoidosis (abbreviated as PSC) as well as normal controls, to identify specific and mutual gene expression patterns as well as signaling pathways involved in disease occurrence and development and to search relevant biomarkers, reliable endpoints as well as potential efficient treatments.…”

“…Although immunological events may determine the granuloma fate, other signaling pathways and factors also play important roles in pathogenesis and/or developmental process of sarcoidosis. Angiogenesis regulated by HIF-1A/VEGF/ inhibitor of growth protein 4 (ING-4) axis may be crucial for the course and outcome of sarcoidosis [22]. Despite these advances, there are no clinically useful biomarkers that can assist the clinician in diagnosis, prognosis or assessment of treatment effects [17,28,38].…”