JACC. Advances · 2025
Sodium-Glucose Cotransporter Inhibition Preserves Apolipoprotein M During Acute Inflammation in Mice and Humans.
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Valenzuela Ripoll Carla, Lotfinaghsh Aynaz, Guo Zhen, Kumari Tripti, Miyata Kana N, Sargazi Alireza, Ozcan Mualla, Diab Ahmed, Ataran Anahita, Hajirezaei Hamidreza, Rashidi Omid, Yu Wenjing, Cho Yoonje, Kovacs Attila, Weinheimer Carla, Nigro Jess, Cases Olivier, Kozyraki Renata, Oscarsson Jan, Esterline Russell, Levi Moshe, Berger Justin H, Schilling Joel D, Apte Rajendra S, Sardiello Marco, Peikert Alexander, Kosiborod Mikhail, Adamo Luigi, Lowenstein Charlie, Christoffersen Christina, Cho Jaehyung, Javaheri Ali
Аннотация
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 (Lrp2KO) mice (n = 5-8/group), Ly6G-Cre LoxP-STOP-TdTomato mice (n = 3-5/group), ApomKO mice (n = 3-5/group), and ApomTG 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.
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 (Lrp2KO) mice (n = 5-8/group), Ly6G-Cre LoxP-STOP-TdTomato mice (n = 3-5/group), ApomKO mice (n = 3-5/group), and ApomTG 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.