Department of Cardiovascular Physiology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
PLoS Biol. 2020 Dec 9;18(12):e3001037. doi: 10.1371/journal.pbio.3001037. eCollection 2020 Dec.
More than 20 years ago, Seta and colleagues hypothesized that cytokines, which are activated by myocardial injury, significantly drive heart failure progression and would therefore be effective targets to treat cardiac dysfunction. Unfortunately, several clinical trials inhibiting key cytokines like tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (Il-1β) turned out negative or even revealed adverse clinical effects. Providing a potential mechanistic explanation for the ineffectiveness of TNF-α blockade in heart failure, novel findings demonstrate that the membrane-bound precursor form of TNF-α, transmembrane TNF-α (tmTNF-α), mediates cardioprotective effects during pressure overload-induced cardiac remodeling. This study suggests that preventing tmTNF-α cleavage by targeting the TNF-α converting enzyme (TACE) rather than inhibiting TNF-α signaling altogether might be a valuable therapeutic approach.
20 多年前，Seta 及其同事假设，心肌损伤激活的细胞因子可显著促进心力衰竭进展，因此是治疗心脏功能障碍的有效靶点。遗憾的是，几项抑制关键细胞因子（如肿瘤坏死因子-α (TNF-α) 和白细胞介素 1β (Il-1β)）的临床试验结果为阴性，甚至出现了不良的临床效果。这些新发现为 TNF-α 阻断在心力衰竭中无效提供了潜在的机制解释，表明 TNF-α 的膜结合前体形式，跨膜 TNF-α（tmTNF-α），在压力超负荷诱导的心脏重构期间介导心脏保护作用。这项研究表明，通过靶向 TNF-α 转化酶（TACE）而不是完全抑制 TNF-α 信号来防止 tmTNF-α 裂解可能是一种有价值的治疗方法。
