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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism
  • Blood Glucose / metabolism
  • DNA Damage*
  • Disease Models, Animal
  • Endothelin-1 / genetics*
  • Endothelin-1 / metabolism
  • Endothelin-Converting Enzymes
  • Histones / metabolism
  • Immunohistochemistry
  • Insulin / blood
  • Lung / metabolism*
  • Male
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism
  • Obesity / blood
  • Obesity / genetics*
  • Obesity / metabolism
  • Phosphoproteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats, Zucker
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic*

Substances

  • Blood Glucose
  • Endothelin-1
  • Histones
  • Insulin
  • Phosphoproteins
  • RNA, Messenger
  • gamma-H2AX protein, rat
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • Endothelin-Converting Enzymes