TY - JOUR
T1 - 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
AU - Adluri, Ram Sudheer
AU - Thirunavukkarasu, Mahesh
AU - Dunna, Nageswara Rao
AU - Zhan, Lijun
AU - Oriowo, Babatunde
AU - Takeda, Kotaro
AU - Sanchez, Juan A.
AU - Otani, Hajime
AU - Maulik, Gautam
AU - Fong, Guo Hua
AU - Maulik, Nilanjana
PY - 2011/10/1
Y1 - 2011/10/1
N2 - 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.
AB - 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.
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U2 - 10.1089/ars.2010.3769
DO - 10.1089/ars.2010.3769
M3 - Article
C2 - 21083501
AN - SCOPUS:80051977344
SN - 1523-0864
VL - 15
SP - 1789
EP - 1797
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 7
ER -