Targeting TACE, a novel approach to the treatment of sympathetic excitation in heart failure.

心力衰竭（HF）是一种毁灭性的疾病。虚弱、死亡和伴随的经济负担 与HF相关的所有研究都表明需要新的治疗方法来更有效地解决这个问题。增加 外周和中枢神经系统中的促炎细胞因子（PIC），特别是肿瘤坏死 因子-α（TNF-α）与HF的病理生理学有关。然而，针对肿瘤坏死因子的抗肿瘤坏死因子临床试验 HF的外周表现未能表现出有益的意义，这表明HF的机制可能与其自身免疫性有关。 TNF-α未受到挑战。我们之前的研究发现，TNF-α在 在HF大鼠模型中，脑的心血管/神经系统相关区域， 交感神经兴奋最近，我们的初步数据表明，TACE，一种TNF-α 转化酶在下丘脑室旁核和穹窿下器中上调 (SFO)并可改变HF大鼠的心血管功能和交感神经驱动。不像其他 在细胞因子中，TNF-α最初作为跨膜蛋白（tmTNF-α）产生。TACE负责 裂解tmTNF-α释放其成熟形式可溶性TNF-α（sTNF-α），介导炎症和 免疫反应。进一步的证据表明sTNF-α主要与TNF受体1结合， tmTNF-α优先与TNF-α结合， 受体2（TNFR 2）显示抗炎和保护作用。该项目将强调以下方面的作用： 脑TACE在TNF-α诱导的炎症机制中驱动HF中的神经体液激活。使用 多方面的方法，包括电生理学，分子生物学，免疫细胞化学，药理学， 和生化，本项目将确定1）TACE是否调节 HF中SFO和PVN中sTNF-α和tmTNF-α之间的平衡，以及涉及的细胞类型; 2）是否 脑内TACE活性增加和/或TNFR 2表达减少有助于神经体液免疫反应。 3）抑制TACE或激活脑中的TNFR 2是否对HF中的兴奋具有有益作用; 心力衰竭患者的心功能和存活率。这些研究将描述一个以前未被认识到的大脑的作用， TACE在HF的神经体液激活中的作用，并将确定一种新的抗TNF药理学靶点。 HF的干预。该研究项目的完成将为抗细胞因子 HF的治疗策略，也可能对其他心血管疾病（如高血压）产生影响 和代谢性疾病如肥胖症或糖尿病。

Heart failure (HF) is a devastating disease. Debilitation, mortality, and concomitant economic burden associated with HF all point to the need for new therapies to address this problem more effectively. Increased pro-inflammatory cytokines (PICs) in periphery and the central nervous system, particularly tumor necrosis factor-α (TNF-α), have been implicated in the pathophysiology of HF. However, anti-TNF clinical trials targeting peripheral manifestations of HF have failed to exhibit beneficial significance, indicating that the mechanisms of TNF-α have not been challenged. Our previous study discovered that TNF-α increases in cardiovascular/autonomic-related regions of the brain in a rat model of HF and contribute significantly to sympathetic excitation in that setting. More recently, our preliminary data indicated that TACE, a TNF-α converting enzyme, is upregulated in the paraventricular nucleus (PVN) of hypothalamus and subfornical organ (SFO) of the brain, and can alter cardiovascular function and sympathetic drive in HF rats. Unlike other cytokines, TNF-α is initially produced as a transmembrane protein (tmTNF-α). TACE is responsible for the cleavage of tmTNF-α to release its mature form, the soluble TNF-α (sTNF-α), to mediate inflammatory and immune responses. Further evidence indicated that sTNF-α binds predominantly to the TNF receptor 1 (TNFR1) to elicit pro-inflammatory and toxic responses and that tmTNF-α binds preferentially to the TNF receptor 2 (TNFR2) to display an anti-inflammatory and protective role. This project will underline the role of the brain TACE in TNF-α–induced inflammatory mechanisms driving the neurohumoral activation in HF. Using a multifaceted approach including electrophysiology, molecular biology, immunocytochemistry, pharmacology, and biochemistry in sham-operated and HF rats, this project will determine 1) whether TACE regulates the balance between sTNF-α and tmTNF-α in SFO and PVN in HF, and what cell types are involved; 2) whether increased TACE activity and/or decreased TNFR2 expression in brain contribute to the neurohumoral excitation in HF; 3) whether inhibition of TACE or activation of TNFR2 in the brain has a beneficial effect on cardiac function and survival rate in HF. These studies will characterize a previously unrecognized role of brain TACE in neurohumoral activation in HF and will identify a novel anti-TNF target for pharmacological intervention of HF. Completion of this research project will provide important insights into the anti-cytokine therapeutic strategy in HF and may also have implications in other cardiovascular disorders like hypertension and metabolic diseases like obesity or diabetes.