Sodium-Glucose Cotransporter Inhibition Preserves Apolipoprotein M During Acute Inflammation in Mice and Humans

Carla Valenzuela Ripoll; Aynaz Lotfinaghsh; Zhen Guo; Tripti Kumari; Kana N Miyata; Alireza Sargazi; Mualla Ozcan; Ahmed Diab; Anahita Ataran; Hamidreza Hajirezaei; Omid Rashidi; Wenjing Yu; Yoonje Cho; Attila Kovacs; Carla Weinheimer; Jess Nigro; Olivier Cases; Renata Kozyraki; Jan Oscarsson; Russell Esterline; Moshe Levi; Justin H Berger; Joel D Schilling; Rajendra S Apte; Marco Sardiello; Alexander Peikert; Mikhail Kosiborod; Luigi Adamo; Charlie Lowenstein; Christina Christoffersen; Jaehyung Cho; Ali Javaheri

doi:10.1016/j.jacadv.2025.101839

Sodium-Glucose Cotransporter Inhibition Preserves Apolipoprotein M During Acute Inflammation in Mice and Humans

Carla Valenzuela Ripoll, Aynaz Lotfinaghsh, Zhen Guo^*, Tripti Kumari, Kana N Miyata, Alireza Sargazi, Mualla Ozcan, Ahmed Diab, Anahita Ataran, Hamidreza Hajirezaei, Omid Rashidi, Wenjing Yu, Yoonje Cho, Attila Kovacs, Carla Weinheimer, Jess Nigro, Olivier Cases, Renata Kozyraki, Jan Oscarsson, Russell EsterlineMoshe Levi, Justin H Berger, Joel D Schilling, Rajendra S Apte, Marco Sardiello, Alexander Peikert, Mikhail Kosiborod, Luigi Adamo, Charlie Lowenstein, Christina Christoffersen, Jaehyung Cho, Ali Javaheri

^*Corresponding author for this work

Department of Clinical Biochemistry

5 Citations (Scopus)

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 (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.

Original language	English
Article number	101839
Journal	JACC: Advances
Volume	4
Issue number	6 Pt 2
DOIs	https://doi.org/10.1016/j.jacadv.2025.101839
Publication status	Published - Jun 2025

Keywords

apolipoprotein M
endothelial vascular integrity
LRP2
SGLT2

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Valenzuela Ripoll, C., Lotfinaghsh, A., Guo, Z., Kumari, T., Miyata, K. N., 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., ... Javaheri, A. (2025). Sodium-Glucose Cotransporter Inhibition Preserves Apolipoprotein M During Acute Inflammation in Mice and Humans. JACC: Advances, 4(6 Pt 2), Article 101839. https://doi.org/10.1016/j.jacadv.2025.101839

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 2025, 'Sodium-Glucose Cotransporter Inhibition Preserves Apolipoprotein M During Acute Inflammation in Mice and Humans', JACC: Advances, vol. 4, no. 6 Pt 2, 101839. https://doi.org/10.1016/j.jacadv.2025.101839

@article{90f217e97b954162ba8f7099d0a16e58,

title = "Sodium-Glucose Cotransporter Inhibition Preserves Apolipoprotein M During Acute Inflammation in Mice and Humans",

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 (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.",

keywords = "apolipoprotein M, endothelial vascular integrity, LRP2, SGLT2",

author = "\{Valenzuela Ripoll\}, Carla and Aynaz Lotfinaghsh and Zhen Guo and Tripti Kumari and Miyata, \{Kana N\} and Alireza Sargazi and Mualla Ozcan and Ahmed Diab and Anahita Ataran and Hamidreza Hajirezaei and Omid Rashidi and Wenjing Yu and Yoonje Cho and Attila Kovacs and Carla Weinheimer and Jess Nigro and Olivier Cases and Renata Kozyraki and Jan Oscarsson and Russell Esterline and Moshe Levi and Berger, \{Justin H\} and Schilling, \{Joel D\} and Apte, \{Rajendra S\} and Marco Sardiello and Alexander Peikert and Mikhail Kosiborod and Luigi Adamo and Charlie Lowenstein and Christina Christoffersen and Jaehyung Cho and Ali Javaheri",

year = "2025",

month = jun,

doi = "10.1016/j.jacadv.2025.101839",

language = "English",

volume = "4",

journal = "JACC: Advances",

issn = "2772-963X",

publisher = "Elsevier BV",

number = "6 Pt 2",

}

TY - JOUR

T1 - Sodium-Glucose Cotransporter Inhibition Preserves Apolipoprotein M During Acute Inflammation in Mice and Humans

AU - Valenzuela Ripoll, Carla

AU - Lotfinaghsh, Aynaz

AU - Guo, Zhen

AU - Kumari, Tripti

AU - Miyata, Kana N

AU - Sargazi, Alireza

AU - Ozcan, Mualla

AU - Diab, Ahmed

AU - Ataran, Anahita

AU - Hajirezaei, Hamidreza

AU - Rashidi, Omid

AU - Yu, Wenjing

AU - Cho, Yoonje

AU - Kovacs, Attila

AU - Weinheimer, Carla

AU - Nigro, Jess

AU - Cases, Olivier

AU - Kozyraki, Renata

AU - Oscarsson, Jan

AU - Esterline, Russell

AU - Levi, Moshe

AU - Berger, Justin H

AU - Schilling, Joel D

AU - Apte, Rajendra S

AU - Sardiello, Marco

AU - Peikert, Alexander

AU - Kosiborod, Mikhail

AU - Adamo, Luigi

AU - Lowenstein, Charlie

AU - Christoffersen, Christina

AU - Cho, Jaehyung

AU - Javaheri, Ali

PY - 2025/6

Y1 - 2025/6

N2 - 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.

AB - 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.

KW - apolipoprotein M

KW - endothelial vascular integrity

KW - LRP2

KW - SGLT2

UR - https://www.scopus.com/pages/publications/105007696864

U2 - 10.1016/j.jacadv.2025.101839

DO - 10.1016/j.jacadv.2025.101839

M3 - Journal article

C2 - 40579057

SN - 2772-963X

VL - 4

JO - JACC: Advances

JF - JACC: Advances

IS - 6 Pt 2

M1 - 101839

ER -

Sodium-Glucose Cotransporter Inhibition Preserves Apolipoprotein M During Acute Inflammation in Mice and Humans

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