SGLT-2 Inhibition with Dapagliflozin Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Cardiomyopathy in Mice with Type 2 Diabetes. Further Augmentation of the Effects with Saxagliptin, a DPP4 Inhibitor

Yumei Ye, Mandeep Bajaj, Hsiu Chiung Yang, Jose R. Perez-Polo, Yochai Birnbaum

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39 Citations (Scopus)

Abstract

Purpose: We assessed whether (1) dapagliflozin (Dapa, an SGLT2-inhibitor) attenuates the deterioration of heart function Nlrp3 and inflammasome activation in diabetic mice. (2) The effects can be augmented with saxagliptin (Saxa), a DDP4-inhibitor. (3) Dapa effect is possibly SGLT2-independent on cardiofibroblasts in vitro. Methods: Type 2 diabetic (BTBR ob/ob) and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Glucose tolerance test and echocardiogram were performed. Cardiofibroblasts from WT and BTBR hearts were incubated with Dapa and exposed to LPS. Results: Left ventricular ejection fraction (LVEF) was 81 ± 1% in the WT and 53 ± 1% in the T2D-cont mice. Dapa and Dapa+Saxa improved LVEF to 68 ± 1 and 74.6 ± 1% in the BTBR mice (p < 0.001). The mRNA levels of NALP3, ASC, IL-1β, IL-6, caspase-1, and TNFα were significantly higher in the BTBR compared to the WT hearts; and Dapa and Dapa+Saxa significantly attenuated these levels. Likewise, protein levels of NLRP3, TNFα, and caspase-1 were higher in the BTBR compared to the WT hearts and Dapa, and to a greater extent Dapa+Saxa, attenuated the increase in the BTBR mice. Collagen-1 and collagen-3 mRNA levels significantly increased in the BTBR mice and these increases were attenuated by Dapa and Dapa+Saxa. P-AMPK/total-AMPK ratio was significantly lower in the BTBR mice than in the WT mice. Dapa and Dapa+Saxa equally increased the ratio in the BTBR mice. This in vitro study showed that NALP3, ASC, IL-1β, and caspase-1 mRNA levels were higher in the BTBR cardiofibroblasts and attenuated with Dapa. The effect was AMPK-dependent and SGLT1-independent. Conclusions: Dapa attenuated the activation of the inflammasome, fibrosis, and deterioration of LVEF in BTBR mice. The anti-inflammatory, anti-fibrotic effects are likely SGLT2- and glucose-lowering-independent, as they were replicated in the in vitro model. The effects on remodeling were augmented when Saxa was added to Dapa. Yet, adding Saxa to Dapa did not result in a greater effect on myocardial fibrosis and collagen levels.

Original languageEnglish (US)
Pages (from-to)119-132
Number of pages14
JournalCardiovascular Drugs and Therapy
Volume31
Issue number2
DOIs
StatePublished - Apr 1 2017

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Diabetic Cardiomyopathies
Inflammasomes
Type 2 Diabetes Mellitus
Caspase 1
AMP-Activated Protein Kinases
Stroke Volume
Collagen
Interleukin-1
Messenger RNA
Fibrosis
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
saxagliptin
Glucose Tolerance Test
Interleukin-6
Anti-Inflammatory Agents

Keywords

  • Diabetes mellitus
  • DPP-4 inhibitor
  • Fibrosis
  • Inflammation
  • SGLT-2 inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

Cite this

@article{6d4b543ccbb140eaae48130435ed0f04,
title = "SGLT-2 Inhibition with Dapagliflozin Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Cardiomyopathy in Mice with Type 2 Diabetes. Further Augmentation of the Effects with Saxagliptin, a DPP4 Inhibitor",
abstract = "Purpose: We assessed whether (1) dapagliflozin (Dapa, an SGLT2-inhibitor) attenuates the deterioration of heart function Nlrp3 and inflammasome activation in diabetic mice. (2) The effects can be augmented with saxagliptin (Saxa), a DDP4-inhibitor. (3) Dapa effect is possibly SGLT2-independent on cardiofibroblasts in vitro. Methods: Type 2 diabetic (BTBR ob/ob) and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Glucose tolerance test and echocardiogram were performed. Cardiofibroblasts from WT and BTBR hearts were incubated with Dapa and exposed to LPS. Results: Left ventricular ejection fraction (LVEF) was 81 ± 1{\%} in the WT and 53 ± 1{\%} in the T2D-cont mice. Dapa and Dapa+Saxa improved LVEF to 68 ± 1 and 74.6 ± 1{\%} in the BTBR mice (p < 0.001). The mRNA levels of NALP3, ASC, IL-1β, IL-6, caspase-1, and TNFα were significantly higher in the BTBR compared to the WT hearts; and Dapa and Dapa+Saxa significantly attenuated these levels. Likewise, protein levels of NLRP3, TNFα, and caspase-1 were higher in the BTBR compared to the WT hearts and Dapa, and to a greater extent Dapa+Saxa, attenuated the increase in the BTBR mice. Collagen-1 and collagen-3 mRNA levels significantly increased in the BTBR mice and these increases were attenuated by Dapa and Dapa+Saxa. P-AMPK/total-AMPK ratio was significantly lower in the BTBR mice than in the WT mice. Dapa and Dapa+Saxa equally increased the ratio in the BTBR mice. This in vitro study showed that NALP3, ASC, IL-1β, and caspase-1 mRNA levels were higher in the BTBR cardiofibroblasts and attenuated with Dapa. The effect was AMPK-dependent and SGLT1-independent. Conclusions: Dapa attenuated the activation of the inflammasome, fibrosis, and deterioration of LVEF in BTBR mice. The anti-inflammatory, anti-fibrotic effects are likely SGLT2- and glucose-lowering-independent, as they were replicated in the in vitro model. The effects on remodeling were augmented when Saxa was added to Dapa. Yet, adding Saxa to Dapa did not result in a greater effect on myocardial fibrosis and collagen levels.",
keywords = "Diabetes mellitus, DPP-4 inhibitor, Fibrosis, Inflammation, SGLT-2 inhibitor",
author = "Yumei Ye and Mandeep Bajaj and Yang, {Hsiu Chiung} and Perez-Polo, {Jose R.} and Yochai Birnbaum",
year = "2017",
month = "4",
day = "1",
doi = "10.1007/s10557-017-6725-2",
language = "English (US)",
volume = "31",
pages = "119--132",
journal = "Cardiovascular Drugs and Therapy",
issn = "0920-3206",
publisher = "Kluwer Academic Publishers",
number = "2",

}

TY - JOUR

T1 - SGLT-2 Inhibition with Dapagliflozin Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Cardiomyopathy in Mice with Type 2 Diabetes. Further Augmentation of the Effects with Saxagliptin, a DPP4 Inhibitor

AU - Ye, Yumei

AU - Bajaj, Mandeep

AU - Yang, Hsiu Chiung

AU - Perez-Polo, Jose R.

AU - Birnbaum, Yochai

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Purpose: We assessed whether (1) dapagliflozin (Dapa, an SGLT2-inhibitor) attenuates the deterioration of heart function Nlrp3 and inflammasome activation in diabetic mice. (2) The effects can be augmented with saxagliptin (Saxa), a DDP4-inhibitor. (3) Dapa effect is possibly SGLT2-independent on cardiofibroblasts in vitro. Methods: Type 2 diabetic (BTBR ob/ob) and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Glucose tolerance test and echocardiogram were performed. Cardiofibroblasts from WT and BTBR hearts were incubated with Dapa and exposed to LPS. Results: Left ventricular ejection fraction (LVEF) was 81 ± 1% in the WT and 53 ± 1% in the T2D-cont mice. Dapa and Dapa+Saxa improved LVEF to 68 ± 1 and 74.6 ± 1% in the BTBR mice (p < 0.001). The mRNA levels of NALP3, ASC, IL-1β, IL-6, caspase-1, and TNFα were significantly higher in the BTBR compared to the WT hearts; and Dapa and Dapa+Saxa significantly attenuated these levels. Likewise, protein levels of NLRP3, TNFα, and caspase-1 were higher in the BTBR compared to the WT hearts and Dapa, and to a greater extent Dapa+Saxa, attenuated the increase in the BTBR mice. Collagen-1 and collagen-3 mRNA levels significantly increased in the BTBR mice and these increases were attenuated by Dapa and Dapa+Saxa. P-AMPK/total-AMPK ratio was significantly lower in the BTBR mice than in the WT mice. Dapa and Dapa+Saxa equally increased the ratio in the BTBR mice. This in vitro study showed that NALP3, ASC, IL-1β, and caspase-1 mRNA levels were higher in the BTBR cardiofibroblasts and attenuated with Dapa. The effect was AMPK-dependent and SGLT1-independent. Conclusions: Dapa attenuated the activation of the inflammasome, fibrosis, and deterioration of LVEF in BTBR mice. The anti-inflammatory, anti-fibrotic effects are likely SGLT2- and glucose-lowering-independent, as they were replicated in the in vitro model. The effects on remodeling were augmented when Saxa was added to Dapa. Yet, adding Saxa to Dapa did not result in a greater effect on myocardial fibrosis and collagen levels.

AB - Purpose: We assessed whether (1) dapagliflozin (Dapa, an SGLT2-inhibitor) attenuates the deterioration of heart function Nlrp3 and inflammasome activation in diabetic mice. (2) The effects can be augmented with saxagliptin (Saxa), a DDP4-inhibitor. (3) Dapa effect is possibly SGLT2-independent on cardiofibroblasts in vitro. Methods: Type 2 diabetic (BTBR ob/ob) and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Glucose tolerance test and echocardiogram were performed. Cardiofibroblasts from WT and BTBR hearts were incubated with Dapa and exposed to LPS. Results: Left ventricular ejection fraction (LVEF) was 81 ± 1% in the WT and 53 ± 1% in the T2D-cont mice. Dapa and Dapa+Saxa improved LVEF to 68 ± 1 and 74.6 ± 1% in the BTBR mice (p < 0.001). The mRNA levels of NALP3, ASC, IL-1β, IL-6, caspase-1, and TNFα were significantly higher in the BTBR compared to the WT hearts; and Dapa and Dapa+Saxa significantly attenuated these levels. Likewise, protein levels of NLRP3, TNFα, and caspase-1 were higher in the BTBR compared to the WT hearts and Dapa, and to a greater extent Dapa+Saxa, attenuated the increase in the BTBR mice. Collagen-1 and collagen-3 mRNA levels significantly increased in the BTBR mice and these increases were attenuated by Dapa and Dapa+Saxa. P-AMPK/total-AMPK ratio was significantly lower in the BTBR mice than in the WT mice. Dapa and Dapa+Saxa equally increased the ratio in the BTBR mice. This in vitro study showed that NALP3, ASC, IL-1β, and caspase-1 mRNA levels were higher in the BTBR cardiofibroblasts and attenuated with Dapa. The effect was AMPK-dependent and SGLT1-independent. Conclusions: Dapa attenuated the activation of the inflammasome, fibrosis, and deterioration of LVEF in BTBR mice. The anti-inflammatory, anti-fibrotic effects are likely SGLT2- and glucose-lowering-independent, as they were replicated in the in vitro model. The effects on remodeling were augmented when Saxa was added to Dapa. Yet, adding Saxa to Dapa did not result in a greater effect on myocardial fibrosis and collagen levels.

KW - Diabetes mellitus

KW - DPP-4 inhibitor

KW - Fibrosis

KW - Inflammation

KW - SGLT-2 inhibitor

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