Brown Adipose Tissue and Cardioprotection

棕色脂肪组织与心脏保护

• 批准号: 9503528
• 负责人: MARIELLE SCHERRER-CROSBIE
• 金额: $ 39.11万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9503528
• 关键词: Brown; Adipose; Tissue; Cardioprotection

 DESCRIPTION (provided by applicant): While the thermogenic properties of brown adipose tissue (BAT) are well known, we recently discovered previously unknown cardioprotective properties of BAT. Mice deficient in the uncoupling protein 1 (UCP1), a protein synthetized by BAT and required for BAT thermogenic function, developed increased cardiomyocyte (CM) injury in a model of catecholamine-induced cardiomyopathy. Cardiomyocyte injury was decreased by transplantation of BAT from WT mice into UCP1-deficient (UCP1-/-) mice, suggesting that functional BAT protects against catecholamine-induced cardiac injury. In Preliminary Studies, we demonstrated that UCP1-/- mice (with dysfunctional BAT) developed greater myocardial infarction (MI) size than WT mice and had a lower level of left ventricular (LV) phosphorylated endothelial nitric oxide synthase (S1177P-NOS3) after ischemia- reperfusion (I/R) injury. We identified bone morphogenetic protein 3b (BMP-3b) as an adipokine secreted by BAT that may mediate BAT-related cardioprotection. BMP-3b increased S1177P-NOS3, decreased apoptosis in serum-deprived rat neonatal CMs and decreased MI size after I/R in WT mice in vivo. The objective of the proposed research is to investigate the cardioprotective effects of BAT and BMP-3b in cardiac I/R injury. To further investigate the cardioprotective role of BAT in I/R injury, we will determine whether UCP1- deficiency induces greater adverse LV remodeling after I/R injury, independent of MI size. We will determine whether restoring functional BAT in UCP1-/- mice and increasing functional BAT in WT mice limit MI size. In these studies, we will transplant BAT from WT mice into UCP1-/- and WT mice prior to myocardial injury. Using CM- specific NOS3-/- mice, we will explore the role of the NOS3 pathway in the cardioprotective effect of BAT. By studying BMP-3b-/- mice, we will elucidate the role of BMP-3b in I/R injury and whether BMP-3b is the adipokine in BAT that is required to limit I/R injury by studying BMP-3b-/- mice. Finally, we will investigate the mechanisms underlying the cardioprotective effects of BMP-3b and explore the potential role of BMP-3b as a treatment for I/R induced CM injury. We will assess the role of the NOS3 pathway in the cardioprotective effect of BMP-3B using both isolated mouse adult CMs and the in vivo I/R model in WT, BMP-3b-/- and CM-specific NOS3-/- mice. As a first step toward applying the results to humans, we will investigate whether BMP-3b is secreted by human brown adipocytes. We will test the effects of varying BMP-3b dose, and time of delivery relative to onset of injury, on the extent of myocardial damage in the in vivo murine I/R model. Successful completion of these aims will define and elucidate a novel cardioprotective effect of BAT in myocardial I/R injury and will characterize a previously unknown cardioprotective adipokine secreted by BAT, BMP-3b. The proposal is a first step toward identifying new cardioprotective therapies that may decrease myocardial I/R.

 描述（由申请人提供）：虽然棕色脂肪组织（BAT）的产热特性是众所周知的，但我们最近发现了BAT以前未知的心脏保护特性。解偶联蛋白1（UCP 1）是BAT合成的一种蛋白质，是BAT产热功能所必需的，缺乏UCP 1的小鼠在儿茶酚胺诱导的心肌病模型中出现了心肌细胞（CM）损伤增加。将WT小鼠的BAT移植到UCP 1缺陷（UCP 1-/-）小鼠中可减少心肌细胞损伤，这表明功能性BAT可防止儿茶酚胺诱导的心脏损伤。在初步研究中，我们证明了UCP 1-/-小鼠（BAT功能障碍）比WT小鼠发生更大的心肌梗死（MI）面积，并且在缺血-再灌注（I/R）损伤后左心室（LV）磷酸化内皮一氧化氮合酶（S1177 P-NOS 3）水平较低。我们鉴定了骨形态发生蛋白3b（BMP-3b）作为BAT分泌的脂肪因子，其可能介导BAT相关的心脏保护作用。BMP-3b增加S1177 P-NOS 3，减少血清剥夺大鼠新生CM的凋亡，并减少WT小鼠体内I/R后MI的大小。本研究的目的是探讨BAT和BMP-3b在心脏I/R损伤中的心脏保护作用。为了进一步研究BAT在I/R损伤中的心脏保护作用，我们将确定UCP 1缺乏是否在I/R损伤后诱导更大的不利的LV重构，而与MI大小无关。我们将确定恢复UCP 1-/-小鼠中的功能BAT和增加WT小鼠中的功能BAT是否限制MI大小。在这些研究中，我们将在心肌损伤之前将WT小鼠的BAT移植到UCP 1-/-和WT小鼠中。利用CM特异性NOS 3-/-小鼠，我们将探索NOS 3通路在BAT的心脏保护作用中的作用。通过研究BMP-3b-/-小鼠，我们将阐明BMP-3b在I/R损伤中的作用，以及BMP-3b是否是BAT中限制I/R损伤所需的脂肪因子。最后，我们将研究BMP-3b的心脏保护作用的机制，并探讨BMP-3b作为I/R诱导的CM损伤的治疗的潜在作用。我们将使用分离的小鼠成年CM和WT、BMP-3b-/-和CM特异性NOS 3-/-小鼠的体内I/R模型来评估NOS 3通路在BMP-3B的心脏保护作用中的作用。作为将结果应用于人类的第一步，我们将研究BMP-3b是否由人类棕色脂肪细胞分泌。我们将测试不同的BMP-3b剂量的影响，相对于损伤的发生时间，在体内小鼠I/R模型的心肌损伤的程度。这些目标的成功完成将定义和阐明BAT在心肌I/R损伤中的新型心脏保护作用，并将表征BAT分泌的先前未知的心脏保护脂肪因子BMP-3b。该提案是确定可能减少心肌I/R的新心脏保护疗法的第一步。