SLC31A1 knockdown mitigates post-MI heart failure via regulation of copper metabolism
Qi Wei1, Huanyu Zhou2, Jie Sun3
1Department of Cardiology, First Hospital of Jilin University, Changchun, Jilin, China.
Insights
Copper overload causes cuproptosis, worsening heart failure after heart attacks. Solute carrier family 31 member 1 (SLC31A1) drives this by activating NLRP3/HMGB1, promoting macrophage cuproptosis and heart failure. Targeting SLC31A1 may treat heart failure.
Area of Science:
- Cardiovascular Biology
- Cellular Metabolism
- Inflammation Research
Background:
- Cuproptosis, a form of cell death induced by copper overload, contributes to cardiovascular diseases, particularly heart failure (HF) post-acute myocardial infarction (AMI).
- Solute carrier family 31 member 1 (SLC31A1) is a key transporter regulating intracellular copper uptake.
Purpose of the Study:
- To investigate the role of SLC31A1 in the development of HF following AMI.
- To elucidate the underlying molecular mechanisms by which SLC31A1 influences post-AMI HF.
Main Methods:
- Established an *in vivo* mouse model of post-AMI HF by ligating the left anterior descending coronary artery.
- Utilized short hairpin RNA targeting SLC31A1, the copper chelator ATTM, and the NLRP3 agonist nigericin for *in vivo* and *in vitro* experiments.
- Induced *in vitro* hypoxia in RAW264.7 macrophages and co-cultured them with cardiomyocytes to validate findings.
Main Results:
- SLC31A1 was upregulated in macrophages from mice with post-AMI HF; its knockdown ameliorated cardiomyocyte apoptosis and HF.
- SLC31A1 knockdown reduced macrophage cuproptosis and HMGB1 release by inactivating the NLRP3 inflammasome, thereby decreasing inflammation and cardiomyocyte apoptosis.
- Copper chelator ATTM also reduced macrophage cuproptosis and cardiomyocyte apoptosis, consistent with *in vitro* findings.
Conclusions:
- SLC31A1 promotes disease progression in HF after AMI by activating NLRP3/HMGB1-dependent macrophage cuproptosis.
- SLC31A1 emerges as a potential therapeutic target and biomarker for HF post-AMI.
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.
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