Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-1 -/-) Attenuates ex vivo myocardial ischemia/reperfusion injury through hypoxia-inducible factor-1α transcription factor and its target genes in mice

Ram Sudheer Adluri, Mahesh Thirunavukkarasu, Nageswara Rao Dunna, Lijun Zhan, Babatunde Oriowo, Kotaro Takeda, Juan A. Sanchez, Hajime Otani, Gautam Maulik, Guo Hua Fong, Nilanjana Maulik

Research output: Contribution to journalArticlepeer-review

Abstract

Hypoxia-inducible transcription factor (HIF)-prolyl hydroxylases domain (PHD-1-3) are oxygen sensors that regulate the stability of the HIFs in an oxygen-dependent manner. Suppression of PHD enzymes leads to stabilization of HIFs and offers a potential treatment option for many ischemic disorders, such as peripheral artery occlusive disease, myocardial infarction, and stroke. Here, we show that homozygous disruption of PHD-1 (PHD-1 -/-) could facilitate HIF-1α-mediated cardioprotection in ischemia/reperfused (I/R) myocardium. Wild-type (WT) and PHD-1 -/- mice were randomized into WT time-matched control (TMC), PHD-1 -/- TMC (PHD1TMC), WT I/R, and PHD-1 -/- I/R (PHD1IR). Isolated hearts from each group were subjected to 30min of global ischemia followed by 2h of reperfusion. TMC hearts were perfused for 2h 30min without ischemia. Decreased infarct size (35%±0.6% vs. 49%±0.4%) and apoptotic cardiomyocytes (106±13 vs. 233±21 counts/100 high-power field) were observed in PHD1IR compared to wild-type ischemia/reperfusion (WTIR). Protein expression of HIF-1α was significantly increased in PHD1IR compared to WTIR. mRNA expression of β-catenin (1.9-fold), endothelial nitric oxide synthase (1.9-fold), p65 (1.9-fold), and Bcl-2 (2.7-fold) were upregulated in the PHD1IR compared with WTIR, which was studied by real-time quantitative polymerase chain reaction. Further, gel-shift analysis showed increased DNA binding activity of HIF-1α and nuclear factor-kappaB in PHD1IR compared to WTIR. In addition, nuclear translocation of β-catenin was increased in PHD1IR compared with WTIR. These findings indicated that silencing of PHD-1 attenuates myocardial I/R injury probably by enhancing HIF-1α/β-catenin/endothelial nitric oxide synthase/nuclear factor-kappaB and Bcl-2 signaling pathway.

Original languageEnglish (US)
Pages (from-to)1789-1797
Number of pages9
JournalAntioxidants and Redox Signaling
Volume15
Issue number7
DOIs
StatePublished - Oct 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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