Brown Adipose Tissue and Cardioprotection

棕色脂肪组织与心脏保护

• 批准号: 9324424
• 负责人: MARIELLE SCHERRER-CROSBIE
• 金额: $ 0.66万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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 2016-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324424
• 关键词: Adipocytes; Adult; Apoptosis; Blood; Brown Fat; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Catecholamines; Contrast echocardiography procedure; Cyclic GMP; Dose; Echocardiography; Functional disorder; Health; Heart; Heart Abnormalities; Human; Injury; Ischemia; Left; Left Ventricular Hypertrophy; Left Ventricular Remodeling; Measurement; Measures; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; NOS3 gene; Neonatal; Pathway interactions; Plasma; Property; Proteins; Rattus; Reperfusion Injury; Reperfusion Therapy; Research; Role; Serum; Signal Transduction Pathway; Soluble Guanylate Cyclase; Testing; Time; Tissues; Transplantation; Ventricular; growth differentiation factor 10; heart metabolism; hemodynamics; in vivo; mouse model; myocardial damage; myocardial infarct sizing; novel; research study; uncoupling protein 1

 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）的生热特性众所周知，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 (UCP1) 是一种由 BAT 合成的蛋白质，也是 BAT 生热功能所必需的，缺乏解偶联蛋白 1 (UCP1) 的小鼠在儿茶酚胺诱导的心肌病模型中心肌细胞 (CM) 损伤增加。将 WT 小鼠的 BAT 移植到 UCP1 缺陷 (UCP1-/-) 小鼠中可减少心肌细胞损伤，这表明功能性 BAT 可以防止儿茶酚胺诱导的心脏损伤。在初步研究中，我们证明 UCP1-/- 小鼠（BAT 功能障碍）比 WT 小鼠出现更大的心肌梗塞（MI），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（S1177P-NOS3）水平较低。我们鉴定出骨形态发生蛋白 3b (BMP-3b) 是 BAT 分泌的脂肪因子，可能介导 BAT 相关的心脏保护作用。 BMP-3b 增加 S1177P-NOS3，减少血清剥夺大鼠新生 CM 的细胞凋亡，并减少 WT 小鼠 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 UCP1 缺乏是否会在 I/R 损伤后诱导更大的不利左室重塑，而与 MI 大小无关。我们将确定恢复 UCP1-/- 小鼠的功能性 BAT 和增加 WT 小鼠的功能性 BAT 是否会限制 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 UCP1-/- 和 WT 小鼠中。使用CM特异性NOS3-/-小鼠，我们将探讨NOS3通路在BAT的心脏保护作用中的作用。通过研究BMP-3b-/-小鼠，我们将通过研究BMP-3b-/-小鼠来阐明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 心脏保护作用的机制，并探讨 BMP-3b 作为治疗 I/R 引起的 CM 损伤的潜在作用。我们将使用分离的小鼠成年 CM 和 WT、BMP-3b-/- 和 CM 特异性 NOS3-/- 小鼠的体内 I/R 模型来评估 NOS3 通路在 BMP-3B 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。我们将在体内小鼠 I/R 模型中测试不同 BMP-3b 剂量和相对于损伤发生的给药时间对心肌损伤程度的影响。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性脂肪因子 BMP-3b。该提案是确定可减少心肌缺血再灌注的新心脏保护疗法的第一步。