ADAMTS7 selective inhibitor BAY-9835 alleviates acute myocardial infarction by suppressing the NF-κB-mediated...

Cardiomyocyte death and functional loss following acute myocardial infarction (AMI) are major causes of post-MI heart dysfunction, yet effective drug treatments remain limited. Previous studies have suggested that plasma ADAMTS7 levels may correlate with poor outcomes in ST-segment elevation MI, but the underlying molecular mechanisms are unclear, and whether pharmacological inhibition of ADAMTS7 can improve AMI symptoms is unknown.

AMI was induced in C57BL/6 mice via ligation of the left anterior descending (LAD) coronary artery. For in vitro studies, AC16 cells were subjected to oxygen-glucose deprivation (OGD) to establish a cellular injury model. Mice were treated with BAY-9835 at doses of 0.1, 0.3, or 0.9 mg/kg/day via intraperitoneal injection. Transcriptomic analysis was performed to identify potential molecular mechanisms.

Both in vivo and in vitro experiments demonstrated a significant upregulation of ADAMTS7 levels following MI or OGD. BAY-9835 treatment significantly improved left ventricular systolic function and reduced infarct size in mice, while non-cytotoxic concentrations of the compound alleviated OGD-induced cardiomyocyte injury in a dose-dependent manner. Transcriptomic analysis identified the NF-κB-pyroptosis pathway as a key regulatory mechanism. Specifically, BAY-9835 effectively inhibited P65 phosphorylation and reduced the expression of pyroptosis marker proteins. Notably, pharmacological activation of NF-κB abolished the protective effects of BAY-9835 in both experimental systems.

This study revealed that ADAMTS7 promotes myocardial injury and cardiac dysfunction following AMI by activating NF-κB-mediated pyroptosis. These effects can be mitigated by the selective ADAMTS7 inhibitor BAY-9835. Therefore, ADAMTS7 may serve as a promising therapeutic target for the treatment of MI.