Key result
Targeting the TNF-α converting enzyme (TACE) to prevent transmembrane TNF-α cleavage mediates cardioprotective effects during pressure overload-induced cardiac remodeling in preclinical models.
Targeting TACE to prevent tmTNF-α cleavage may offer a novel therapeutic approach for heart failure, explaining the failure of previous broad TNF-α inhibitors.
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.
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Dittrich et al. (2020) conducted an editorial in Heart failure. TACE inhibition was evaluated. Targeting the TNF-α converting enzyme (TACE) to prevent transmembrane TNF-α cleavage mediates cardioprotective effects during pressure overload-induced cardiac remodeling in preclinical models.
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