Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy.
Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy.
复制标题
DOI：
10.1161/circulationaha.109.922427
复制
发表时间：
2010-09-07
期刊：
影响因子：
37.8
通讯作者：
Kaelin WG Jr
中科院分区：
文献类型：
--
作者：
Moslehi J;Minamishima YA;Shi J;Neuberg D;Charytan DM;Padera RF;Signoretti S;Liao R;Kaelin WG Jr
缺血性心肌病是心力衰竭的主要原因，也是发病率和死亡率的重要原因。在这种情况下，左心功能不全的程度通常与明显梗死的组织的数量不成比例，氧气和营养物质的输送减少如何导致收缩能力受损仍未完全清楚。PhD Pro羟基酶是一种氧敏感酶，它将氧可获得性的变化转化为HIF转录因子稳定性的变化，HIF转录因子是促进在低氧环境中生存的基因的主要调节因子。我们发现，随着时间的推移，心脏特异的PHD失活会导致超微结构、组织学和功能的变化，使人想起缺血性心肌病。此外，心肌细胞中稳定的缺氧诱导因子α变异体的慢性表达也导致扩张型心肌病。PHD活性的持续丧失和随后的HIF激活，就像在慢性缺血的背景下发生的那样，足以解释慢性冠状动脉疾病患者心脏的许多变化。
Ischemic cardiomyopathy is the major cause of heart failure and a significant cause of morbidity and mortality. The degree of left ventricular dysfunction in this setting is often out of proportion to the amount of overtly infarcted tissue and how decreased delivery of oxygen and nutrients leads to impaired contractility remains incompletely understood. The PHD prolyl hydroxylases are oxygen-sensitive enzymes that transduce changes in oxygen availability into changes in the stability of the HIF transcription factor, a master regulator of genes that promote survival in a low oxygen-environment. We found that cardiac-specific PHD inactivation causes ultrastructural, histological, and functional changes reminiscent of ischemic cardiomyopathy over time. Moreover, chronic expression of a stabilized HIFα variant in cardiomyocytes also led to dilated cardiomyopathy. Sustained loss of PHD activity and subsequent HIF activation, as would occur in the setting of chronic ischemia, is sufficient to account for many of the changes in the hearts of individuals with chronic coronary artery disease.