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SHR Neuro Cancer Cardio Lipid Metab Microb

Valenzuela, Ripoll, C; Lotfinaghsh, A; Guo, Z; Kumari, T; Miyata, KN; Sargazi, A; Ozcan, M; Diab, A; Ataran, A; Hajirezaei, H; Rashidi, O; Yu, W; Cho, Y; Kovacs, A; Weinheimer, C; Nigro, J; Cases, O; Kozyraki, R; Oscarsson, J; Esterline, R; Levi, M; Berger, JH; Schilling, JD; Apte, RS; Sardiello, M; Peikert, A; Kosiborod, M; Adamo, L; Lowenstein, C; Christoffersen, C; Cho, J; Javaheri, A.
Sodium-Glucose Cotransporter Inhibition Preserves Apolipoprotein M During Acute Inflammation in Mice and Humans.
JACC Adv. 2025; 4(6 Pt 2):101839 Doi: 10.1016/j.jacadv.2025.101839 [OPEN ACCESS]
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Co-authors Med Uni Graz: Peikert Alexander
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Abstract:: BACKGROUND: Sodium-glucose cotransporter inhibitors (SGLT2is) reduce inflammation and maintain vascular integrity. Apolipoprotein M (ApoM) is crucial for vascular integrity via sphingosine-1-phosphate (S1P) signaling and is inversely linked with mortality in sepsis and COVID-19. OBJECTIVES: The authors tested if SGLT2i (dapagliflozin [Dapa]) increases ApoM in mice using lipopolysaccharide (LPS) and in humans with COVID-19. METHODS: Diet-induced obese mice (n = 14-15/group), proximal tubule-specific knockout of the multiligand protein receptor Lrp2 (Lrp2^KO) mice (n = 5-8/group), Ly6G-Cre LoxP-STOP-TdTomato mice (n = 3-5/group), Apom^KO mice (n = 3-5/group), and Apom^TG mice (n = 3-5/group) were randomized to receive either vehicle or Dapa (1.25 mg/kg daily) for 4 days before LPS (10 mg/kg IP). Outcomes included ApoM protein levels (Western and enzyme-linked immunosorbent assay) and intravital microscopy to assess endothelial leak and neutrophil behavior. Plasma samples from ACTIV-4a participants (standard of care, n = 37; standard of care + SGLT2i, n = 15) were analyzed for circulating ApoM by enzyme-linked immunosorbent assay. Statistical analyses included two-way analysis of variance for mice and t-test or Mann-Whitney test for humans. RESULTS: Dapa restored circulating ApoM levels in LPS-treated mice (0.017 vs 0.035 [a.u./μL], P = 0.0489) and increased ApoM levels in patients randomized to SGLT2i (0.5240 vs 0.6537 [μM], P = 0.0101). LRP2 knockout blocked Dapa's effect on ApoM. In vitro, Dapa stimulated Lrp2-dependent uptake of ApoM-GFP. Dapa attenuated vascular leak induced by LPS in an ApoM-dependent manner. CONCLUSIONS: SGLT2i maintains Lrp2 levels, preserving ApoM and promoting endothelial barrier integrity in acute inflammation, indicating a novel protective mechanism of SGLT2i through ApoM preservation.
Find related publications in this database (Keywords): apolipoprote in M; endothelial vascular integrity; LRP2; SGLT2