Oriowo Babatunde, Thirunavukkarasu Mahesh, Selvaraju Vaithinathan, Adluri Ram Sudheer, Zhan Lijun, Takeda Kotaro, Fong Guo-Hua, Sanchez Juan A, Maulik Nilanjana
Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut Health Center, Farmington Connecticut, USA.
Curr Pharm Des. 2014;20(9):1305-10. doi: 10.2174/13816128113199990549.
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.
关键的氧感应分子，脯氨酰羟化酶结构域1-3酶（PHD1-3），在缺氧条件下调节缺氧诱导因子（HIF）。在心肌病和缺血再灌注损伤的情况下，PHD3表达升高，导致HIF激活减少。PHD3在心肌损伤中的作用尚不清楚。因此，我们旨在确定在小鼠中缺失PHD3对心肌梗死（MI）后HIF-1α和其他相关通路的影响。结扎野生型和脯氨酰羟化酶3基因敲除（PHD3⁻/⁻）小鼠的左冠状动脉（LAD）以诱导心肌梗死。电泳迁移率变动分析显示，与MI后野生型（WT）小鼠相比，PHD3⁻/⁻小鼠中HIF-1α的DNA结合活性显著增加。PHD3⁻/⁻MI组的纤维化也减少。MI后7天，与WTMI组相比，观察到毛细血管/小动脉密度增加。与WT相比，通过超声心动图评估，接受MI的PHD3⁻/⁻小鼠的心脏功能（射血分数和缩短分数）也有所改善。蛋白质印迹分析显示，PHD3⁻/⁻MI组中VEGF、Ang-1和Bcl-2表达增加。总之，PHD3基因的缺失导致梗死后血管生成增加和心脏功能改善，从而为缺血性心肌病的药物治疗提供了一个潜在靶点。
