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.
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.
authors: Babatunde
authors: B
authors: Oriowo
authors: Mahesh
authors: M
authors: Thirunavukkarasu
authors: Vaithinathan
authors: V
authors: Selvaraju
authors: Ram Sudheer
authors: RS
authors: Adluri
authors: Lijun
authors: L
authors: Zhan
authors: Kotaro
authors: K
authors: Takeda
authors: Guo-Hua
authors: GH
authors: Fong
authors: Juan A
authors: JA
authors: Sanchez
authors: Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut Health Center, Farmington Connecticut, USA. nmaulik@neuron.uchc.edu.
authors: Nilanjana
authors: N
authors: Maulik
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D017353:Gene Deletion; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C522721:PHD1 protein, mouse; C522722:PHD3 protein, mouse; D011393:Procollagen-Proline Dioxygenase