Fatty Acids: Ischemic Protection and Repair

心脏减少脂肪酸(FAs)的氧化，并在缺血时切换到更高的葡萄糖利用率。而当 这个过程允许用更少的氧气生产更多的ATP，这是以限制使用为代价的 Fas，心脏能量的主要底物。我们假设这会导致燃料匮乏，特别是在 血流减少会降低能量底物的利用率。如果这个假设是正确的，那么存储 心脏中更多的甘油三酯将导致减少缺血性损害；我们推测这是 “肥胖悖论”，患有更多缺血性疾病的肥胖者 心肌梗死存活率。 这项建议包括研究心脏与心脏之间的基本和临床相关关系的实验。 FA代谢与心功能。具体地说，我们将使用PI创建的小鼠来研究 甘油三酯的储存和脂质摄取改变了心脏对缺血/再灌注的反应。此外，我们还将测试 髓系细胞正常摄取FAs所需基因的缺失是否会影响它们向 交替激活和修复表型。这些研究将包括心脏基因的评估。 变化和脂类组学，并将利用示踪动力学来评估葡萄糖和脂类的摄取和氧化，以及 来确定他们的下游产品。这些实验将需要两个实验室的合作：一个 拥有心脏脂质代谢方面的专业知识，第二位拥有缺血/再灌流模型和 底物代谢分析。本申请的三个目标如下：目标1.确定 增加心肌细胞储存甘油三酯是否改善对缺血的反应。目标2.评估 心脏脂肪摄取减少的小鼠是否改变了对缺血的反应。目的3.评估缺血 巨噬细胞特异性脂蛋白脂酶缺失和分化簇对小鼠的损伤与修复 (CD)36.实验将使用几种因转基因表达而储存的更多的心脏甘油三酯 二酰甘油酰基转移酶1和过氧化体增殖物激活受体γ的表达 脂肪蛋白脂酶和CD36的组织特异性缺失导致FAs的摄取。这些研究将说明 减少缺血损伤和改善受损心肌修复的可能代谢途径。

The heart reduces fatty acid (FAs) oxidation and switches to greater glucose utilization with ischemia. While this process allows more ATP production with less oxygen use, it occurs at the expense of limiting the use of FAs, the major substrates for cardiac energy. We hypothesize that this leads to fuel deprivation, especially as blood flow reduction decreases energetic substrate availability. If this hypothesis is correct, then storage of more triglyceride in the heart would lead to reduced ischemic damage; this we speculate is the reason for the “obesity paradox” in which obese humans who have more ischemic disease also have increased post myocardial infarction survival. This proposal includes experiments to study basic and clinically relevant relationships between heart FA metabolism and heart function. Specifically, we will use mice created by the PI to study how changes in triglyceride stores and lipid uptake alter cardiac response to ischemia/reperfusion. In addition, we will test whether deletion of genes required for normal uptake of FAs by myeloid cells affects their conversion to an alternatively activated and reparative phenotype. These studies will include assessment of cardiac gene changes and lipidomics and will utilize tracer kinetics to assess uptake and oxidation of glucose and lipids, and to determine their downstream products. The experiments will require the collaboration of two laboratories: one with expertise in heart lipid metabolism and the second with expertise in ischemic/reperfusion models and analysis of substrate metabolism. The three aims of this application are the following: Aim 1. To determine whether increased cardiomyocyte storage of triglyceride improves response to ischemia. Aim 2. To assess whether mice with reduced heart lipid uptake have altered response to ischemia. Aim 3. To assess ischemic injury and repair in mice with macrophage-specific deletions of lipoprotein lipase and cluster of differentiation (CD)36. The experiments will use several lines greater cardiac triglyceride stores due to transgenic expression of diacylglycerol acyl transferase 1 and peroxisomal proliferator activated receptor γ, and mice with reduced uptake of FAs due to tissue specific deletions of lipoprotein lipase and CD36. These studies will illustrate possible metabolic approaches to reducing ischemic injury and improving repair of damaged myocardium.