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

被引：77

作者：

Adluri, Ram Sudheer ^{[1
]}

Thirunavukkarasu, Mahesh ^{[1
]}

Dunna, Nageswara Rao ^{[1
]}

Zhan, Lijun ^{[1
]}

Oriowo, Babatunde ^{[1
,2
]}

Takeda, Kotaro ^{[3
]}

Sanchez, Juan A. ^{[2
]}

Otani, Hajime ^{[4
]}

Maulik, Gautam ^{[5
]}

Fong, Guo-Hua ^{[3
]}

Maulik, Nilanjana ^{[1
]}

机构：

[1] Univ Connecticut, Sch Med, Mol Cardiol & Angiogenesis Lab, Dept Surg, Farmington, CT 06032 USA

[2] St Marys Hosp, Dept Surg, Waterbury, CT USA

[3] Univ Connecticut, Sch Med, Dept Cell Biol, Farmington, CT 06032 USA

[4] Kansai Med Univ, Dept Thorac & Cardiovasc Surg 2, Moriguchi, Osaka 570, Japan

[5] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

来源：

ANTIOXIDANTS & REDOX SIGNALING | 2011年 / 15卷 / 07期

关键词：

ISCHEMIA-REPERFUSION INJURY; NF-KAPPA-B; NITRIC-OXIDE SYNTHASE; FACTOR-I; INDUCED APOPTOSIS; OXYGEN SENSORS; FACTOR-ALPHA; ANGIOGENESIS; INHIBITION; RAT;

D O I：

10.1089/ars.2010.3769

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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-1 alpha-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 30 min of global ischemia followed by 2h of reperfusion. TMC hearts were perfused for 2h 30 min 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-1 alpha was significantly increased in PHD1IR compared to WTIR. mRNA expression of beta-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 withWTIR, which was studied by real-time quantitative polymerase chain reaction. Further, gel-shift analysis showed increased DNA binding activity of HIF-1 alpha and nuclear factor-kappaB in PHD1IR compared to WTIR. In addition, nuclear translocation of beta-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-1 alpha/beta-catenin/endothelial nitric oxide synthase/nuclear factor-kappaB and Bcl-2 signaling pathway. Antioxid. Redox Signal. 15, 1789-1797.

引用

页码：1789 / 1797

页数：9

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