Depletion of PHD3 protects heart from ischemia/reperfusion injury by inhibiting cardiomyocyte apoptosis

Liang Xie, Xinchun Pi, Zhongjing Wang, Jun He, Monte Willis, Cam Patterson

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

PHD3, a member of a family of Prolyl-4 Hydroxylase Domain (PHD) proteins, has long been considered a pro-apoptotic protein. Although the pro-apoptotic effect of PHD3 requires its prolyl hydroxylase activity, it may be independent of HIF-1α, the common substrate of PHDs. PHD3 is highly expressed in the heart, however, its role in cardiomyocyte apoptosis remains unclear. This study was undertaken to determine whether inhibition or depletion of PHD3 inhibits cardiomyocyte apoptosis and attenuates myocardial injury induced by ischemia-reperfusion (I/R). PHD3 knockout mice and littermate controls were subjected to left anterior descending (LAD) coronary artery ligation for 40. min followed by reperfusion. Histochemical analysis using Evan's Blue, triphenyl-tetrazolium chloride and TUNEL staining, demonstrated that myocardial injury and cardiomyocyte apoptosis induced I/R injury were significantly attenuated in PHD3 knockout mice. PHD3 knockout mice exhibited no changes in HIF-1α protein level, the expression of some HIF target genes or the myocardium capillary density at physiological condition. However, depletion of PHD3 further enhanced the induction of HIF-1α protein at hypoxic condition and increased expression of HIF-1α inhibited cardiomyocyte apoptosis induced by hypoxia. In addition, it has been demonstrated that PHD3 plays an important role in ATR/Chk1/p53 pathway. Consistently, a prolyl hydroxylase inhibitor or depletion of PHD3 significantly inhibits the activation of Chk1 and p53 in cardiomyocytes and the subsequent apoptosis induced by doxorubicin, hydrogen peroxide or hypoxia/reoxygenation. Taken together, these data suggest that depletion of PHD3 leads to increased stabilization of HIF-1α and inhibition of DNA damage response, both of which may contribute to the cardioprotective effect seen with depletion of PHD3.

Original languageEnglish (US)
Pages (from-to)156-165
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume80
DOIs
StatePublished - Mar 1 2015
Externally publishedYes

Fingerprint

Reperfusion Injury
Cardiac Myocytes
Apoptosis
Knockout Mice
Prolyl Hydroxylases
Prolyl-Hydroxylase Inhibitors
Evans Blue
Apoptosis Regulatory Proteins
In Situ Nick-End Labeling
Doxorubicin
Hydrogen Peroxide
DNA Damage
Reperfusion
Ligation
Chlorides
Coronary Vessels
Myocardium
Proteins
Staining and Labeling
Wounds and Injuries

Keywords

  • DNA damage response
  • Hypoxia inducible factor
  • Ischemia-reperfusion
  • Oxidative stress
  • Prolyl-4 hydroxylase domain protein

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Depletion of PHD3 protects heart from ischemia/reperfusion injury by inhibiting cardiomyocyte apoptosis. / Xie, Liang; Pi, Xinchun; Wang, Zhongjing; He, Jun; Willis, Monte; Patterson, Cam.

In: Journal of Molecular and Cellular Cardiology, Vol. 80, 01.03.2015, p. 156-165.

Research output: Contribution to journalArticle

Xie, Liang ; Pi, Xinchun ; Wang, Zhongjing ; He, Jun ; Willis, Monte ; Patterson, Cam. / Depletion of PHD3 protects heart from ischemia/reperfusion injury by inhibiting cardiomyocyte apoptosis. In: Journal of Molecular and Cellular Cardiology. 2015 ; Vol. 80. pp. 156-165.
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