Abstract P1152: Molecular Regulation Of Ferroptosis In The Type 1 Diabetic Heart

Abstract

Background/Hypothesis: The molecular mechanisms underpinning ferroptosis, a newly emerged mechanism of myocardial cell death, remains unclear in the T1DM heart. Although the targeted deletion of matrix metalloproteinase-9 (MMP9) is cardioprotective, the role of MMP9 in T1DM-induced cardiac ferroptosis is unknown. We hypothesize that the lack of MMP9 mitigates ferroptosis in the T1DM heart. Methods/Results: We randomly selected 15-week-old male Ins2 +/- Akita (T1DM) and age and gender-matched Ins2 +/+ littermate WT mice to examine T1DM-induced cardiac ferroptosis. We used our novel Akita/MMP9KO (DKO) mice to investigate the specific effect of MMP9 deficiency on T1DM-induced cardiac ferroptosis. Following the guidelines on myocardial cell death , we evaluated ferroptosis in the heart (LV) of WT, Akita, DKO, and MMP9KO mice. The comparison of protein levels in (i) Akita vs. WT and (ii) Akita vs. DKO (n=3-6) revealed that the lack of MMP9 prevents T1DM-induced upregulation of iron import [Transferrin Receptor (TFR): (i) +2.44-fold, (ii) -1.78-fold], downregulation of iron export [Ferroportin-1: (i) -3.20-fold, (ii) +2.20-fold], amplification of lipid peroxidation via a decrease in Glutathione Peroxidase-4 (GPX4) [(i) -1.95-fold, (ii) +2.01-fold], antioxidants [ {Superoxide dismutase-1 (SOD1): (i) -1.1-fold, (ii) +1.00-fold} and SOD2 {(i) -1.58-fold, (ii) +1.01-fold}], and an increase in Lysophosphatidylcholine Acyltransferase-3 (LPCAT3) [(i) +3.14-fold, (ii) -2.09-fold] in the heart. Conclusion: We reveal the mechanisms by which MMP9 deficiency mitigates ferroptosis in the T1DM heart (Figure 1). This is the first report of MMP9 role in cardiac ferroptosis.