Oxidative DNA damage and DNA mismatch repair pathway play an important role in failing human myocardium

Ruxian Lin, Daqing Gao, Yesong Gu, Pramod Bonde, Torin P. Fitton, Joshua M. Hare, John V. Conte, G. Melville Williams, Chiming Wei

Research output: Contribution to journalArticle

Abstract

Background: Heart failure is approaching epidemic proportions. However, DNA damage in the failing myocardium is not directly addressed yet. 8-Oxo-7,8-dihydrodeoxyguanine (8-oxoG) is a stable marker of DNA damage. The human Mut-Y homologue (hMYH) is a DNA mismatching repair enzyme promoting DNA reconstruction. The current study was designed to investigate whether DNA damage and repair as reflected in the levels of 8-oxoG and hMYH play an important role in the failing myocardium. Methods: Donor and failing human myocardium were obtained from hearts of patients undergoing cardiac transplantation. DNA damage was determined by the presence of 8-oxoG. The protein level, activity, and expression of hMYH were determined by Western blot, the DNA gel-retardation binding assay and immunohistochemical staining (IHCS). The levels of apoptosis and apoptosis-related genes such as p53, p21-WAF, and caspase-3 were determined by TUNEL assay and IHCS. Results: The levels of 8-oxoG indicating DNA damage significantly increased in the myocardium of failing hearts compared with donor subjects. On the other hand, the protein level and activity of the DNA repair enzyme, hMYH, was significantly decreased in CHF patients compared to donor subjects. Furthermore, apoptosis and apoptosis-related genes such as p53, p21-WAF, and caspase-3 were markedly increased in CHF myocardium. Conclusion: Ongoing DNA damage is insufficiently repaired in the myocardium of failing hearts. This appears to be a major pathway responsible for myocardial failure in humans.

Original languageEnglish (US)
Pages (from-to)41-49
Number of pages9
JournalJournal of Cardiothoracic-Renal Research
Volume1
Issue number1
DOIs
StatePublished - Mar 1 2006
Externally publishedYes

Keywords

  • Apoptosis
  • DNA damage
  • DNA repair
  • Heart failure
  • hMYH

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Nephrology
  • Pulmonary and Respiratory Medicine

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