Dapagliflozin improves endothelial integrity and hemodynamics in endotoxin treated mice through an apolipoprotein M dependent pathway

  1. Carla Valenzuela Ripoll
  2. Zhen Guo
  3. Tripti Kumari
  4. Kana N. Miyata
  5. Mualla Ozcan
  6. Ahmed Diab
  7. Amanda Girardi
  8. Li He
  9. Attila Kovacs
  10. Carla Weinheimer
  11. Jess Nigro
  12. Jan Oscarsson
  13. Russell Esterline
  14. Joel Schilling
  15. Mikhail Kosiborod
  16. Christina Christoffersen
  17. Jaehyung Cho
  18. Ali Javaheri
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Abstract

Rationale

Sodium-glucose co-transporter inhibitors (SGLT2i) are under active clinical investigation in patients with acute inflammatory conditions, based on their clinical cardio-and nephroprotective effects, and a pre-clinical study that demonstrated SGLT2i improve renal outcomes and survival in a lipopolysaccharide (LPS) model. However, a unified mechanism that explains how SGLT2i could prevent hemodynamic consequences of inflammatory conditions has not been described. Apolipoprotein M (ApoM) is inversely associated with mortality in inflammatory conditions and improves cardiac function in endotoxin-treated mice via sphingosine-1-phosphate (S1P) signaling.

Objective

Test the hypothesis that pre-treatment with SGLT2i dapagliflozin (Dapa) improves hemodynamics in endotoxin-treated mice via the ApoM/S1P pathway.

Methods and Results

Mice with diet-induced obesity were gavaged with vehicle or Dapa for 4 days prior to LPS (10 mg/kg, IP). We found that mice receiving Dapa restored circulating ApoM levels, likely by increasing expression of the multi-ligand protein receptor megalin in the proximal tubules. Dapa attenuated LPS-induced reductions in cardiac dysfunction including reductions in ejection fraction, cardiac index, and coronary sinus area as well as vascular permeability as ascertained by intravital microscopy. Using both ApoM transgenic and knockout mice and S1P receptor inhibitors, we show that the ApoM/S1P pathway is important for the beneficial effects of Dapa in the LPS model.

Conclusions

In the setting of acute inflammation, our data suggest that SGLT2i maintains levels of megalin, leading to preservation of ApoM, which in turn promotes endothelial barrier integrity and improves hemodynamics. Our studies suggest a novel mechanism by which SGLT2i can preserve intravascular volume in the acute inflammatory setting.

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