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bioRxiv · 10.1101/2022.04.27.489709

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

Valenzuela Ripoll, C.·Guo, Z.·Kumari, T.·Miyata, K. N.·Ozcan, M.·Diab, A.·Girardi, A.·He, L.·Kovacs, A.·Weinheimer, C. J.·Nigro, J.·Oscarsson, J.·Esterline, R.·Schilling, J.·Kosiborod, M.·Christoffersen, C.·Cho, J.·Javaheri, A.
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Abstract

RationaleSodium-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. ObjectiveTest the hypothesis that pre-treatment with SGLT2i dapagliflozin (Dapa) improves hemodynamics in endotoxin-treated mice via the ApoM/S1P pathway. Methods and ResultsMice 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. ConclusionsIn 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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Valenzuela Ripoll, C., Guo, Z., Kumari, T., Miyata, K. N., Ozcan, M., Diab, A., Girardi, A., He, L., Kovacs, A., Weinheimer, C. J., Nigro, J., Oscarsson, J., Esterline, R., Schilling, J., Kosiborod, M., Christoffersen, C., Cho, J., Javaheri, A.. 2022-04-28. Dapagliflozin improves endothelial integrity and hemodynamics in endotoxin treated mice through an apolipoprotein M dependent pathway. https://doi.org/10.1101/2022.04.27.489709

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