TY - JOUR
T1 - 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
AU - Oriowo, Babatunde
AU - Thirunavukkarasu, Mahesh
AU - Selvaraju, Vaithinathan
AU - Adluri, Ram Sudheer
AU - Zhan, Lijun
AU - Takeda, Kotaro
AU - Fong, Guo Hua
AU - Sanchez, Juan A.
AU - Maulik, Nilanjana
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Bcl-2
KW - HIF
KW - Myocardial infarction
KW - Prolyl hydroxylase
KW - VEGF
UR - http://www.scopus.com/inward/record.url?scp=84896350565&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84896350565&partnerID=8YFLogxK
U2 - 10.2174/13816128113199990549
DO - 10.2174/13816128113199990549
M3 - Article
C2 - 23978105
AN - SCOPUS:84896350565
SN - 1381-6128
VL - 20
SP - 1305
EP - 1310
JO - Current pharmaceutical design
JF - Current pharmaceutical design
IS - 9
ER -