Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, 44 Binney St, Boston, MA 02115, USA.
Circulation. 2010 Sep 7;122(10):1004-16. doi: 10.1161/CIRCULATIONAHA.109.922427. Epub 2010 Aug 23.
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 Prolyl Hydroxylase Domain-Containing Protein (PHD) prolyl hydroxylases are oxygen-sensitive enzymes that transduce changes in oxygen availability into changes in the stability of the hypoxia-inducible factor 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, long-term expression of a stabilized hypoxia-inducible factor alpha variant in cardiomyocytes also led to dilated cardiomyopathy.
Sustained loss of PHD activity and subsequent hypoxia-inducible factor activation, as would occur in the setting of chronic ischemia, are sufficient to account for many of the changes in the hearts of individuals with chronic coronary artery disease.
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，左心室功能障碍的程度往往与明显梗死组织的数量不成比例，而氧和营养物质的输送减少如何导致收缩功能障碍仍不完全清楚。脯氨酰羟化酶结构域包含蛋白（PHD）脯氨酰羟化酶是氧敏感酶，可将氧可用性的变化转化为缺氧诱导因子转录因子稳定性的变化，缺氧诱导因子转录因子是促进低氧环境中生存的基因的主要调节剂。
我们发现，心脏特异性 PHD 失活会导致随着时间的推移出现类似于缺血性心肌病的超微结构、组织学和功能变化。此外，心肌细胞中稳定的缺氧诱导因子α变体的长期表达也导致扩张型心肌病。
慢性缺血情况下持续丧失 PHD 活性和随后的缺氧诱导因子激活足以解释慢性冠状动脉疾病患者心脏的许多变化。
