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. 2015 Mar;34(3):170-7.
doi: 10.1089/dna.2014.2705. Epub 2014 Dec 17.

Transcriptional alterations of ET-1 axis and DNA damage in lung tissue of a rat obesity model

Silvia Del Ry  1 , Manuela Cabiati, Costanza Salvadori, Letizia Guiducci, Chiara Caselli, Tommaso Prescimone, Maria Sole Facioni, Alessia Azzarà, Anna Chiaramonte, Stefano Mazzoni, Fabrizio Bruschi, Daniela Giannessi, Roberto Scarpato
Affiliations

Transcriptional alterations of ET-1 axis and DNA damage in lung tissue of a rat obesity model

Silvia Del Ry et al. DNA Cell Biol. 2015 Mar.

Abstract

Obesity has been implicated in the development of many cancers. This can lead to genome damage, especially in the form of double-strand break, the presence of which is now easily detected through nuclear phosphorylation of histone H2AX (γ-H2AX) focus assay. Recently, the endothelin (ET) axis has also been shown to have a role in the growth and progression of several tumors, including lung cancer. The aim of this study was to evaluate the ET-1 system transcriptional alterations and γ-H2AX in lung tissue of Zucker rats subdivided into obese (O, n=22) and controls (CO, n=18) rats: under either fasting conditions (CO(fc)-O(fc)) or acute hyperglycemia (CO(AH)-O(AH)). Significantly higher prepro-ET-1 (p=0.05) and ET-converting enzyme (ECE)-2 mRNA expression was observed in O with respect to CO. A significant positive association was observed between prepro-ET-1 and ET-A in the whole rat population (p=0.009) or in the obese group alone (p=0.007). The levels of γ-H2AX in O and in O(AH) rats were significantly higher (p=0.019) than in the corresponding CO and CO(AH) rats (p=0.038). The study shows an inappropriate secretion of ET-1 in O animals with a parallel DNA damage in their lungs, providing novel mechanisms by which ET receptor antagonist may exert organ protection.

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Figures

<b>FIG. 1.</b>
FIG. 1.
Photos of lung sections of Zucker rat after immunohistochemistry with γ-H2AX primary antibody detected with an anti-rabbit horseradish peroxidase-conjugated secondary antibody: (A, B), two areas showing several γ-H2AX-positive nuclei; (C, D), two areas showing only hematoxylin-stained nuclei (no γ-H2AX expression). (A–C), 400× magnification; (D), 200× magnification.
<b>FIG. 2.</b>
FIG. 2.
Levels of body weight, blood glucose and insulin in CO and O rats. CO, control lean; O, obese.
<b>FIG. 3.</b>
FIG. 3.
Area under curves (AUC) for glucose in control lean and obese Zucker rats during fasting (COfc and Ofc) or acute hyperglycemia (COAH and OAH).
<b>FIG. 4.</b>
FIG. 4.
mRNA expression of prepro-ET-1, ECE-2, ET-A, and ET-B in pulmonary tissues of control lean and obese Zucker rats. ECE, endothelin-converting enzyme; ET, endothelin.
<b>FIG. 5.</b>
FIG. 5.
Fold change values related to ET-1, ECE-2, ET-A, and ET-B.
<b>FIG. 6.</b>
FIG. 6.
mRNA expression of prepro-ET-1, ECE-2, ET-A, and ET-B in pulmonary tissues of control lean and obese Zucker rats during fasting (COfc and Ofc) and acute hyperglycemia (COAH and OAH). fc, fasting; AH, acute hyperglycemia.
<b>FIG. 7.</b>
FIG. 7.
Levels of γ-H2AX in Zucker rats classified according to obesity condition (lean, CO; obese, O) or glycemia status (fasting, fc; acute hyperglycemia, AH). p=0.019, O rats versus CO rats (ANOVA test).
<b>FIG. 8.</b>
FIG. 8.
Levels of γ-H2AX in lean (CO) and obese (O) Zucker rats stratified according to glycemia status (fasting, COfc and Ofc; acute hyperglycemia, COAH and OAH). p=0.038, OAH rats versus COAH rats (ANOVA test).
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