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

心力衰竭是一种毁灭性的疾病。虚弱、死亡和伴随而来的经济负担 与心力衰竭相关的所有问题都表明需要新的治疗方法来更有效地解决这个问题。增加了 外周和中枢神经系统中的促炎细胞因子，特别是肿瘤坏死 因子-肿瘤坏死因子(α-α)参与了心力衰竭的病理生理过程。然而，针对抗肿瘤坏死因子的临床试验 心力衰竭的外周表现没有表现出有益的意义，表明心力衰竭的机制 肿瘤坏死因子-α尚未受到挑战。我们先前的研究发现，肿瘤坏死因子-α在 在心力衰竭大鼠模型中的心血管/自主神经相关区域，并对 在那个环境中产生共鸣的兴奋。最近，我们的初步数据表明，肿瘤坏死因子-α 转换酶在下丘脑室旁核和穹隆下器上调 并能改变心力衰竭大鼠的心血管功能和交感神经动力。不同于其他 细胞因子，肿瘤坏死因子-α最初以跨膜蛋白的形式产生(tmTNF-α)。TACE负责 切割肿瘤坏死因子-α释放其成熟形式--可溶性肿瘤坏死因子-α(sTNF-α)，以介导炎症和 免疫反应。进一步的证据表明，stf-α主要与ntf受体1结合。 (肿瘤坏死因子受体1)诱导促炎和毒性反应，并且tmTNF-α优先结合肿瘤坏死因子 受体2(TNFR2)具有抗炎和保护作用。该项目将强调 脑动脉化疗栓塞术在肿瘤坏死因子-α诱导的炎症机制中的作用。vbl.使用 包括电生理学、分子生物学、免疫细胞化学、药理学、 在假手术和心力衰竭大鼠中，该项目将确定1)TACE是否调节 STNF-α和tmTNF-α在SFO和PVN中的平衡，以及参与了哪些细胞类型；2) 脑内TACE活性增加和/或TNFR2表达减少与神经体液有关 3)抑制TACE或激活脑组织中的TNFR2是否具有有益的作用 心功能和存活率。这些研究将描述大脑以前未被认识到的作用 TACE对心力衰竭患者神经体液激活的影响及寻找新的抗肿瘤坏死因子的药理学靶点 心衰的干预。这项研究项目的完成将为研究抗细胞因子提供重要的见解 心力衰竭的治疗策略，并可能对高血压等其他心血管疾病也有意义 以及肥胖或糖尿病等代谢性疾病。

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.