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https://doi.org/10.1016/j.bpj.2022.11.778
Copy DOIJournal: Biophysical Journal | Publication Date: Feb 1, 2023 |
License type: publisher-specific-oa |
Hypomagnesemia (HypoMg) is frequently observed in heart failure (HF), and Mg dietary supplementation has shown therapeutic benefits. Previously, we have reported that HypoMg induces cardiac diastolic dysfunction (DD). Transient receptor potential melastatin 7 channel (TRPM7), a Mg transporter with a kinase domain, has shown regulation on Mg homeostasis in cardiomyocytes. In this study, we aim to assess the role of TRPM7 in inflammation and DD. Wild type (WT) C57BL/6J and transgenic TRPM7K1646R mice (with a global homozygous K1646R mutation in the kinase domain, resulting in no kinase activity) were fed with a normal (2 g/kg Mg) or a HypoMg diet (15-30 mg/kg Mg) for 6 weeks. Echocardiography was performed to monitor heart function. Heart tissue were collected for protein levels of TRPM7, IL-1β, and NLRP3. A macrophage cell line Raw264.7 cells were treated with a HypoMg medium (with 0.04 mM Mg) or a normal medium (with 0.81 mM Mg), and macrophage TRPM7 protein levels were tested. IL-1β collected from the culture media was tested with a Mouse IL-1 beta/IL-1F2 Quantikine ELISA Kit. In WT-HypoMg mouse hearts, E/e’ (an indicator for DD obtained from echocardiograph), TRPM7 protein expression, IL-1β, and NLRP3 levels were significantly increased, all of which were suppressed in the TRPM7K1646R-HypoMg hearts. TRPM7 protein levels were also significantly increased in the HypoMg-medium treated macrophages (1.6±0.2-fold, P=0.027). HypoMg increased secreted IL-1β in cultured macrophages (11.8±2.7 pg/µg protein vs. 4.3±0.8 pg/µg protein in the normal medium group, P=0.038). Upregulation of TRPM7 kinase function under HypoMg correlates with macrophage activation, elevated levels of IL-1β, and cardiac DD, suggesting inflammation as a potential mediator of HypoMg-induced DD.
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