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Administrative Supplement to 7R01HL148060-03 Titled: Opposing Effects of Prostaglandin E2 EP3 and EP4 Receptors on Mitochondrial

7R01HL148060-03 的行政补充，标题为：前列腺素 E2 EP3 和 EP4 受体对线粒体的相反作用

基本信息

批准号：
10711712
负责人：
PAMELA HARDING
金额：
$ 7.7万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2024-01-31
项目状态：
已结题

项目摘要

ABSTRACT Heart disease and heart failure are important causes of morbidity and mortality, affecting approximately 300 million people, at an enormous cost. Although current treatments slow the progression of these diseases, there has been little progress in preventing the compensated heart transitioning to that of a failing one. The Prostaglandin E2 (PGE2) receptor subtypes EP3 and EP4 are most abundant in the heart and activate different signaling pathways (Gαi for EP3, Gαs for EP4). Compelling data from my laboratory shows that EP3 expression is increased in the pathologically diseased heart produced by myocardial infarction (MI) or Angiotensin II- dependent hypertension (Ang II-HTN), that stimulation of the EP3 receptor decreases cardiac contractility whereas EP4 increases it and that overexpression of EP4 in the failing heart improves cardiac function. The failing heart switches from fatty acid (FA) oxidation to reliance on glucose. Coupled with this are alterations in mitochondrial function. Thus, mitochondrial dysfunction is an important player in the pathogenesis of heart failure. Our previous gene array data showed dramatic down regulation of mitochondrial genes in mice in which the EP4 receptor was deleted in cardiomyocytes; allowing PGE2 to act via the EP3 receptor and new data shows that an EP3 agonist reduces Complex I activity and ATP levels in adult mouse cardiomyocytes. mRNAs for proteins that alter both FA oxidation and their transport into mitochondria; specifically, carnitine palmitoyl transferase (CPT) were also down regulated in EP4 KO hearts. In other tissues, CPT activity was reportedly regulated by the transcription factor/orphan receptor NR4A2 (Nurr1) in a PGE2-dependent process but whether this occurs in the heart is unstudied. Since heart failure is characterized by reduced FA oxidation, we propose the novel overall hypothesis: EP3 is increased during cardiac injury and impairs mitochondrial function due to reduced fatty acid import via diminished CPT activity. This is mediated by decreased activity of the transcription factor, NR4A2. Ultimately these events contribute to heart failure. To test this hypothesis, we propose 3 aims that will use a new conditional and cardiomyocyte-specific EP3 KO mouse model coupled with an EP3 overexpressing transgenic mouse to determine whether upregulation of cardiomyocyte EP3 contributes to impaired contractile function and reduced mitochondrial function in heart failure caused by Ang II-HTN and MI. The study also examines whether PGE2 via its EP3 receptor reduces import of fatty acids into mitochondria via decreased activity of the transcription factor NR4A2 which subsequently reduces CPT activity; and whether these events reduce subsequent ATP levels. The proposal employs a multidisciplinary approach including physiological, biochemical and imaging studies that will impact the treatment of heart failure.

摘要心脏病和心力衰竭是发病和死亡的重要原因，影响约300人数百万人，付出了巨大的代价。虽然目前的治疗方法减缓了这些疾病的进展，在防止代偿心脏向衰竭心脏过渡方面进展甚微。的前列腺素E2（PGE 2）受体亚型EP 3和EP 4在心脏中最丰富，并激活不同的细胞因子。信号通路（Gαi代表EP 3，Gαs代表EP 4）。我实验室的数据显示，EP 3的表达在心肌梗死（MI）或血管紧张素II引起的病理性心脏病中增加，依赖性高血压（Ang II-HTN），即EP 3受体的刺激会降低心肌收缩力而EP 4则增加了它，并且在衰竭的心脏中EP 4的过表达改善了心脏功能。的衰竭的心脏从脂肪酸（FA）氧化转变为依赖葡萄糖。与此同时，线粒体功能因此，线粒体功能障碍是心脏病发病机制中的重要参与者。失败我们先前的基因阵列数据显示小鼠线粒体基因的显著下调，心肌细胞中的EP 4受体被删除;允许PGE 2通过EP 3受体起作用，新数据显示，显示EP 3激动剂降低成年小鼠心肌细胞中的复合物I活性和ATP水平。mRNAs 对于改变FA氧化及其转运到线粒体的蛋白质;特别是肉毒碱棕榈酰在EP 4 KO心脏中，CPT也下调。据报道，在其他组织中，CPT活性在PGE 2依赖性过程中受转录因子/孤儿受体NR 4A 2（Nurr 1）调节，但是否这发生在心脏是未经研究的。由于心力衰竭的特点是减少FA氧化，我们建议，新的总体假设：EP 3在心脏损伤过程中增加，并由于以下原因损害线粒体功能：通过减少CPT活性减少脂肪酸输入。这是由转录活性降低介导的，因子NR 4A 2。最终，这些事件会导致心力衰竭。为了验证这一假设，我们提出了三个目标该研究将使用一种新的条件性和心肌细胞特异性EP 3 KO小鼠模型，过表达转基因小鼠，以确定心肌细胞EP 3的上调是否有助于在由Ang II-HTN和MI引起的心力衰竭中收缩功能受损和线粒体功能降低。该研究还检查了PGE 2是否通过其EP 3受体减少脂肪酸进入线粒体通过降低转录因子NR 4A 2的活性，其随后降低CPT活性;以及这些事件降低随后的ATP水平。该提案采用多学科方法，包括生理、生化和影像学研究将影响心力衰竭的治疗。