Hypoxia is associated with many disease conditions including myocardial ischemia, the most common cause of dilated cardiomyopathy (DCM) and heart failure. In spite of improvements in the diagnosis and medical treatment, the morbidity and mortality caused by ischemic heart disease remains very high in the United States. Notably, both clinical trials and experimental animal studies indicate that the decrease of oxygen availability is sufficient to induce contractile dysfunction even before substantial ventricular damage, suggesting a direct role of oxygen in tuning cardiac contractility. However, the underlying mechanism remains largely unknown. It is well documented that prolyl hydroxylase domain (PHD) proteins serve as oxygen sensor and play a central role in the beneficial adaptive responses to hypoxia. Paradoxically, we demonstrated recently that combined deletion of PHD2 and PHD3, two most abundant isoforms of PHDs in cardiomyocytes, potentiates cardiomyocyte apoptosis, cardiac hypertrophy and arrhythmia induced by chronic ?-adrenergic stress. In addition, long-term depletion of both PHD2 and PHD3 in the heart results in dilated cardiomyopathy and produces many hallmarks of ischemic heart disease even under non-stressed condition. Collectively, these data strongly suggest that inhibition of PHD enzymatic activity by hypoxia also plays a crucial role in the cardiac dysfunction induced by myocardial ischemia. However, the underlying molecular mechanisms remain poorly understood. Recently, we demonstrated that PHD2 and PHD3 catalyze the prolyl hydroxylation of thyroid hormone receptor alpha (TR-?), a potent transcriptional regulator of phospholamban (PLN), and combined deletion of PHD2 and PHD3 suppresses the transcription of phospholamban (PLN) in cardiomyocytes. Following an unbiased proteomic and liquid chromatography-tandem mass spectrometry (LC- MS/MS) analysis, we discovered another new substrate of PHD2 and PHD3- muscle LIM protein (MLP), a sarcomeric Z-line component. Specifically, PHD2 and PHD3 interact with MLP and promote its hydroxylation. These observations lead us to hypothesize that PHD acts as a central mediator of cardiac function by hydroxylating crucial calcium cycling regulators and sarcomeric proteins, and thereby loss of PHD enzymatic activity plays a causal role in the development of dilated cardiomyopathy induced by PHD2/3 deletion and myocardial ischemia. To test this hypothesis, we propose the following aims: 1) Determine the role of PLN/Ca2+ signaling axis in dilated cardiomyopathy induced by PHD2 and PHD3 deletion; 2) Investigate the role of MLP in dilated cardiomyopathy induced by PHD2 and PHD3 deletion; 3) Elucidate the differential roles of PHD2 and PHD3 and their therapeutic potentials in dilated cardiomyopathy. Collectively, these studies will provide novel and fundamental insights into the role of PHD2/3 in the heart, broaden the functional scope of prolyl hydroxylation, and identify new therapeutic targets for treating heart diseases.
Cardiac diseases are the No.1 killer in America. Dysregulation of Ca2+ signaling plays a pivotal role in the myocardial infarction-induced adverse ventricular remodeling, which includes cardiomyocyte apoptosis, hypertrophy and contractile dysfunction. We will use both in vitro and in vivo models to understand the novel roles of PHD 2 and 3 in cardiac function including the regulation of Ca2+ signaling, sarcomere organization and mitochondrial function, at both normal and disease conditions. These studies will suggest novel therapeutic targets and strategies that can be applied to cardiac diseases.
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