Chronic Inhibition of Hypoxia-inducible Factor Prolyl 4-hydroxylase Improves Ventricular Performance, Remodeling, and Vascularity After Myocardial Infarction in the Rat
Chronic Inhibition of Hypoxia-inducible Factor Prolyl 4-hydroxylase Improves Ventricular Performance, Remodeling, and Vascularity After Myocardial Infarction in the Rat
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DOI：
10.1097/fjc.0b013e3181e2bfef
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发表时间：
2010-08-01
影响因子：
3
通讯作者：
Willette, Robert N.
中科院分区：
文献类型：
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作者：
Bao, Weike;Qin, Pu;Willette, Robert N.
背景：缺氧诱导因子 (HIF) 是转录因子，受 HIF-脯氨酰 4-羟化酶 (PHD) 调节，以响应氧张力的变化。一旦被激活，HIF 在血管生成、红细胞生成、增殖、细胞存活、炎症和能量代谢中发挥重要作用。我们假设 GSK360A 是一种新型口服活性 HIF-PHD 抑制剂，可以促进局部和全身 HIF-1 α 信号传导并保护心肌梗死 (MI) 后衰竭的心脏。方法和结果：GSK360A 是一种有效的（纳摩尔）HIF-PHD 抑制剂 (PHD1>PHD2 = PHD3)，能够激活 HIF-1a 多种细胞类型中的信号通路，包括新生大鼠心室肌细胞和 H9C2 细胞。口服GSK360A（30 mg.kg(-1).d(-1)）的雄性大鼠的促红细胞生成素和血红蛋白循环水平持续升高，心脏和骨骼肌中血氧合酶-1表达增加。在结扎左冠状动脉前降支诱发的心力衰竭伴收缩功能障碍的大鼠模型中，GSK360A 28 天的慢性治疗可防止射血分数进行性降低、心室扩张和肺重量增加，这些现象在媒介物治疗的动物中观察到长达 3 个月。此外，GSK360A 治疗的动物梗塞周围区域的微血管密度增加（>2 倍）。治疗耐受性良好（GSK360A 组的存活率为 89%，安慰剂组的存活率为 82%）。 结论：在已建立的模型中，使用选择性 HIF PHD 抑制剂 (GSK360A) 治疗慢性心肌梗死后，可通过稳定 HIF-1 α 信号传导发挥全身和局部作用，并改善长期心室功能、重构和血管分布。 心室功能障碍。这些结果表明，HIF-PHD 抑制剂可能适合治疗 MI 后重构和心力衰竭。
Background: Hypoxia inducible factors (HIFs) are transcription factors that are regulated by HIF-prolyl 4-hydroxylases (PHDs) in response to changes in oxygen tension. Once activated, HIFs play an important role in angiogenesis, erythropoiesis, proliferation, cell survival, inflammation, and energy metabolism. We hypothesized that GSK360A, a novel orally active HIF-PHD inhibitor, could facilitate local and systemic HIF-1 alpha signaling and protect the failing heart after myocardial infarction (MI).Methods and Results: GSK360A is a potent (nanomolar) inhibitor of HIF-PHDs (PHD1>PHD2 = PHD3) capable of activating the HIF-1a pathway in a variety of cell types including neonatal rat ventricular myocytes and H9C2 cells. Male rats treated orally with GSK360A (30 mg.kg(-1).d(-1)) had a sustained elevation in circulating levels of erythropoietin and hemoglobin and increased hemoxygenase-1 expression in the heart and skeletal muscle. In a rat model of established heart failure with systolic dysfunction induced by ligation of left anterior descending coronary artery, chronic treatment with GSK360A for 28 days prevented the progressive reduction in ejection fraction, ventricular dilation, and increased lung weight, which were observed in the vehicle-treated animals, for up to 3 months. In addition, the microvascular density in the periinfarct region was increased (>2-fold) in GSK360A-treated animals. Treatment was well tolerated (survival was 89% in the GSK360A group vs. 82% in the placebo group).Conclusions: Chronic post-myocardial infarction treatment with a selective HIF PHD inhibitor (GSK360A) exerts systemic and local effects by stabilizing HIF-1 alpha signaling and improves long-term ventricular function, remodeling, and vascularity in a model of established ventricular dysfunction. These results suggest that HIF-PHD inhibitors may be suitable for the treatment of post-MI remodeling and heart failure.