SLC31A1 knockdown mitigates post-MI heart failure via regulation of copper metabolism.

INTRODUCTION: Cuproptosis due to copper overload is a contributor to the progression of cardiovascular diseases, especially heart failure (HF) after acute myocardial infarction (AMI). Solute carrier family 31 member 1 (SLC31A1) is a major Cu2+ transporter responsible for intracellular Cu2+ uptake. In this study, we investigated the role and detailed mechanism of SLC31A1 in post-AMI HF. METHODS: Mouse left anterior descending coronary artery was ligated to produce an in vivo post-AMI HF model. These mice were subjected to treatments with short hairpin RNA targeting SLC31A1, the copper chelator ATTM and the NLRP3 agonist nigericin to elucidate the mechanism of SLC31A1 in post-AMI HF. Additionally, an in vitro model of hypoxia was induced in macrophages RAW264.7, which were then treated with small interfering RNA targeting SLC31A1, ATTM and nigericin, and subsequently co-cultured with cardiomyocytes to validate the SLC31A1 mechanism in vitro. RESULTS: SLC31A1 was up-regulated in macrophages of mice with post-AMI HF , while its knockdown prevented cardiomyocyte apoptosis and post-AMI HF. Mechanistically, SLC31A1 knockdown regulated copper metabolism imbalance to reduce macrophage cuproptosis and HMGB1 release, attenuating inflammatory responses and the resultant cardiomyocyte apoptosis. This could be explained by NLRP3 inflammasome inactivation. Meanwhile, ATTM reduced macrophage cuproptosis and cardiomyocyte apoptosis. These results were reproduced in in vitro studies. Strikingly, NLRP3/HMGB1 activation in vivo partly abolished SLC31A1 knockdown-induced alleviation of macrophage cuproptosis and cardiomyocyte apoptosis. DISCUSSION: SLC31A1 plays a disease-promoting role in HF after AMI by activating NLRP3/HMGB1-dependent macrophage cuproptosis, which is expected to be a potential biomarker for HF.