Brown Adipose Tissue and Cardioprotection

摘要 虽然棕色脂肪组织（BAT）的产热特性是众所周知的，我们最近报道， BAT对儿茶酚胺诱导的心肌损伤的先前未知的心脏保护特性。在 初步研究，支持目前的建议，我们确定了骨形态发生蛋白3b（BMP- 3b）作为心脏保护性脂肪因子，其可介导BAT相关的心脏保护。的目的 建议进一步研究BAT和BMP-3b在小鼠模型中的心脏保护作用。 心肌缺血再灌注损伤。在初步研究中，我们证明， 解偶联蛋白1（UCP 1）缺陷，UCP 1是BAT合成的蛋白质，是BAT产热所需的 功能，在I/R损伤后比WT小鼠发展更大的心肌梗死（MI）尺寸。我们鉴定出BMP-3b， 一种以前未知的心血管特性的蛋白质，作为一种脂肪因子，由 WT小鼠的BAT活化，但UCP 1缺陷小鼠的BAT未活化。我们证明BMP-3b治疗可降低MI， WT小鼠I/R损伤后的大小。在初步研究中，BMP-3b增加了P-Smad 1/5/8的水平， S1177 P-NOS 3，并减少血清剥夺心肌细胞（CM）的凋亡。此外，BMP-3b I/R后左心室（LV）P-Smad 1/5/8和STAT 3水平升高。进一步调查 BAT在I/R损伤中的心脏保护作用，我们将确定是否在UCP 1-/-小鼠中恢复功能性BAT WT小鼠中功能性BAT的增加限制了MI的大小。在这些研究中，我们将从WT小鼠中移植BAT， 在心肌损伤之前，将UCP 1-/-和WT小鼠移植到UCP 1-/-和WT小鼠中。通过研究BMP-3b-/-和BAT特异性BMP-3b-/-小鼠， 我们将阐明BMP-3b是否是BAT中的脂肪因子，BAT是否是 限制I/R损伤。为了研究BMP-3b的心脏保护作用的机制， 将评估BMP、NOS 3和STAT 3通路在BMP-3b的心脏保护作用中的作用 使用分离的成年小鼠CM和体内I/R鼠模型。与BMP-3b结合的CM受体 将被识别。作为将研究结果应用于人类的第一步，我们将研究BMP-3b是否是 由人类棕色脂肪细胞分泌，以及心肌梗死是否增加了BMP-3b在血浆中的表达。 人类病人为了进一步研究BMP-3b治疗I/R损伤的潜在临床适用性，我们 将测试不同的BMP-3b剂量和相对于损伤开始的递送时间对 在体内鼠I/R模型中的心肌损伤。成功完成这些目标将确定和 阐明BAT在心肌I/R损伤中的新型心脏保护作用，并将表征先前的 由BAT分泌的未知心脏保护性脂肪因子BMP-3b。该提案是确定 新的心脏保护疗法可能减少心肌I/R损伤。

Abstract While the thermogenic properties of brown adipose tissue (BAT) are well known, we recently reported previously unknown cardioprotective properties of BAT against catecholamine-induced myocardial injury. In preliminary studies that support the present proposal, we identified bone morphogenetic protein 3b (BMP- 3b) as a cardioprotective adipokine that may mediate BAT-related cardioprotection. The objective of this proposal is to further investigate the cardioprotective effects of BAT and BMP-3b in a murine model of myocardial ischemia-reperfusion (I/R) injury. In preliminary studies, we demonstrated that mice that are deficient in the uncoupling protein 1 (UCP1), a protein synthetized by BAT and required for BAT thermogenic function, develop greater myocardial infarction (MI) size than WT mice after I/R injury. We identified BMP-3b, a protein of previously unknown cardiovascular properties, as an adipokine synthesized and secreted by the activated BAT of WT but not of UCP1-deficient mice. We demonstrated that BMP-3b treatment decreased MI size after I/R injury in WT mice. In preliminary studies, BMP-3b increased the levels of P-Smad1/5/8 and S1177P-NOS3, and decreased apoptosis in serum-deprived cardiomyocytes (CMs). Furthermore, BMP-3b increased left ventricular (LV) P-Smad1/5/8 and STAT3 levels after I/R. To further investigate the cardioprotective role of BAT in I/R injury, 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. By studying BMP-3b-/- and BAT-specific BMP-3b-/- mice, we will elucidate whether BMP-3b is the adipokine in BAT, and BAT the BMP-3b producing tissue that is required to limit I/R injury. To investigate the mechanisms underlying the cardioprotective effects of BMP-3b, the role of the BMP, NOS3 and STAT3 pathways in the cardioprotective effect of BMP-3b will be assessed using both isolated mouse adult CMs and the in vivo I/R murine model. The CM receptors engaged by BMP-3b will be identified. As a first step toward applying the results to humans, we will investigate whether BMP-3b is secreted by human brown adipocytes, and whether myocardial infarction increases BMP-3b in the plasma of human patients. To further investigate the potential clinical applicability of BMP-3b treatment in I/R injury, we will test the effect 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 injury.