Abstract
The key oxygen sensing molecules, Prolyl-hydroxylase domain 1-3 enzymes (PHD1-3), regulate hypoxia-inducible factor (HIF) under hypoxia. In the settings of cardiomyopathy and ischemia-reperfusion injury, PHD3 expression is elevated, resulting in decreased HIF activation. The role of PHD3 in myocardial injury is poorly understood. Hence, we aimed to determine the effects of PHD3 deletion in mice on HIF-1α and other related pathways following myocardial infarction (MI). Left coronary artery (LAD) in both wild type and prolyl hydroxylase 3 knock out (PHD3-/-) mice was ligated to induce myocardial infarction. Electrophoretic mobility shift analysis showed significant increase in DNA-binding activity of HIF-1α in PHD3-/- mice as compared to wild type (WT) mice post MI. The PHD3-/-MI group also showed decreased fibrosis. Seven days after MI, enhanced capillary / arteriolar density was observed compared to WTMI group. PHD3-/- mice subjected to MI also showed improved cardiac functions (Ejection fraction and Fractional shortening), as assessed by echocardiogram, compared to WT. Western blot analysis showed increased VEGF, Ang-1 & Bcl-2 expression in PHD3-/-MI group. In conclusion, ablation of the PHD3 gene resulted in increased angiogenesis and cardiac function after infarction thereby offering a potential target for pharmacological management of ischemic myocardial disease.
Keywords: Angiogenesis, myocardial infarction, Bcl-2, VEGF, HIF, prolyl hydroxylase.
Current Pharmaceutical Design
Title:Targeted Gene Deletion of Prolyl Hydroxylase Domain Protein 3 Triggers Angiogenesis and Preserves Cardiac Function by Stabilizing Hypoxia Inducible Factor 1 Alpha Following Myocardial Infarction
Volume: 20 Issue: 9
Author(s): Babatunde Oriowo, Mahesh Thirunavukkarasu, Vaithinathan Selvaraju, Ram Sudheer Adluri, Lijun Zhan, Kotaro Takeda, Guo-Hua Fong, Juan A. Sanchez and Nilanjana Maulik
Affiliation:
Keywords: Angiogenesis, myocardial infarction, Bcl-2, VEGF, HIF, prolyl hydroxylase.
Abstract: The key oxygen sensing molecules, Prolyl-hydroxylase domain 1-3 enzymes (PHD1-3), regulate hypoxia-inducible factor (HIF) under hypoxia. In the settings of cardiomyopathy and ischemia-reperfusion injury, PHD3 expression is elevated, resulting in decreased HIF activation. The role of PHD3 in myocardial injury is poorly understood. Hence, we aimed to determine the effects of PHD3 deletion in mice on HIF-1α and other related pathways following myocardial infarction (MI). Left coronary artery (LAD) in both wild type and prolyl hydroxylase 3 knock out (PHD3-/-) mice was ligated to induce myocardial infarction. Electrophoretic mobility shift analysis showed significant increase in DNA-binding activity of HIF-1α in PHD3-/- mice as compared to wild type (WT) mice post MI. The PHD3-/-MI group also showed decreased fibrosis. Seven days after MI, enhanced capillary / arteriolar density was observed compared to WTMI group. PHD3-/- mice subjected to MI also showed improved cardiac functions (Ejection fraction and Fractional shortening), as assessed by echocardiogram, compared to WT. Western blot analysis showed increased VEGF, Ang-1 & Bcl-2 expression in PHD3-/-MI group. In conclusion, ablation of the PHD3 gene resulted in increased angiogenesis and cardiac function after infarction thereby offering a potential target for pharmacological management of ischemic myocardial disease.
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Oriowo Babatunde, Thirunavukkarasu Mahesh, Selvaraju Vaithinathan, Adluri Sudheer Ram, Zhan Lijun, Takeda Kotaro, Fong Guo-Hua, Sanchez A. Juan and Maulik Nilanjana, Targeted Gene Deletion of Prolyl Hydroxylase Domain Protein 3 Triggers Angiogenesis and Preserves Cardiac Function by Stabilizing Hypoxia Inducible Factor 1 Alpha Following Myocardial Infarction, Current Pharmaceutical Design 2014; 20 (9) . https://dx.doi.org/10.2174/13816128113199990549
DOI https://dx.doi.org/10.2174/13816128113199990549 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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