PMID- 32335797
OWN - NLM
STAT- MEDLINE
DCOM- 20201127
LR  - 20211204
IS  - 1573-7241 (Electronic)
IS  - 0920-3206 (Linking)
VI  - 34
IP  - 4
DP  - 2020 Aug
TI  - Dapagliflozin and Ticagrelor Have Additive Effects on the Attenuation of the 
      Activation of the NLRP3 Inflammasome and the Progression of Diabetic 
      Cardiomyopathy: an AMPK-mTOR Interplay.
PG  - 443-461
LID - 10.1007/s10557-020-06978-y [doi]
AB  - PURPOSE: Ticagrelor, a P2Y12 receptor antagonist, and dapagliflozin, a 
      sodium-glucose-cotransporter-2 inhibitor, suppress the activation of the NLRP3 
      inflammasome. The anti-inflammatory effects of dapagliflozin depend on AMPK 
      activation. Also, ticagrelor can activate AMPK. We assessed whether dapagliflozin 
      and ticagrelor have additive effects in attenuating the progression of diabetic 
      cardiomyopathy in T2DM mice. METHODS: Eight-week-old BTBR and wild-type mice 
      received no drug, dapagliflozin (1.5 mg/kg/day), ticagrelor (100 mg/kg/day), or 
      their combination for 12 weeks. Heart function was evaluated by echocardiography 
      and heart tissue samples were assessed for fibrosis, apoptosis, qRT-PCR, and 
      immunoblotting. RESULTS: Both drugs attenuated the progression of diabetic 
      cardiomyopathy as evident by improvements in left ventricular end-systolic and 
      end-diastolic volumes and left ventricular ejection fraction, which were further 
      improved by the combination. Both drugs attenuated the activation of the NOD-like 
      receptor 3 (NLRP3) inflammasome and fibrosis. The effect of the combination was 
      significantly greater than each drug alone on myocardial tissue necrotic 
      factoralpha (TNFalpha) and interleukin-6 (IL-6) levels, suggesting additive effects. The 
      combination had also a greater effect on ASC, collagen-1, and collagen-3 mRNA 
      levels than each drug alone. While both drugs activated adenosine mono-phosphate 
      kinase (AMPK), only dapagliflozin activated mTOR and increased RICTOR levels. 
      Moreover, only dapagliflozin decreased myocardial BNP and Caspase-1 mRNA levels, 
      and the effects of dapagliflozin on NLRP3 and collagen-3 mRNA levels were 
      significantly greater than those of ticagrelor. CONCLUSIONS: Both dapagliflozin 
      and ticagrelor attenuated the progression of diabetic cardiomyopathy, the 
      activation of the NLRP3 inflammasome, and fibrosis in BTBR mice with additive 
      effects of the combination. While both dapagliflozin and ticagrelor activated 
      AMPK, only dapagliflozin activated mTOR complex 2 (mTORC2) in hearts of BTBR 
      mice.
FAU - Chen, Huan
AU  - Chen H
AD  - The Department of Biochemistry and Molecular Biology, University of Texas Medical 
      Branch, 301 University Blvd, BSB 648, Galveston, TX, 77555, USA.
AD  - Department of Acupuncture, First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, China.
FAU - Tran, Da
AU  - Tran D
AD  - School of Medicine, University of Texas Medical Branch, Galveston, TX, USA.
FAU - Yang, Hsiu-Chiung
AU  - Yang HC
AD  - Biopharmaceutical R&D, AstraZeneca, Gothenburg, Sweden.
FAU - Nylander, Sven
AU  - Nylander S
AD  - Biopharmaceutical R&D, AstraZeneca, Gothenburg, Sweden.
FAU - Birnbaum, Yochai
AU  - Birnbaum Y
AD  - The Section of Cardiology, Department of Medicine, Baylor College of Medicine, 
      Houston, TX, USA.
FAU - Ye, Yumei
AU  - Ye Y
AD  - The Department of Biochemistry and Molecular Biology, University of Texas Medical 
      Branch, 301 University Blvd, BSB 648, Galveston, TX, 77555, USA. yumye@utmb.edu.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cardiovasc Drugs Ther
JT  - Cardiovascular drugs and therapy
JID - 8712220
RN  - 0 (Benzhydryl Compounds)
RN  - 0 (Glucosides)
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Nlrp3 protein, mouse)
RN  - 0 (Purinergic P2Y Receptor Antagonists)
RN  - 0 (Sodium-Glucose Transporter 2 Inhibitors)
RN  - 1ULL0QJ8UC (dapagliflozin)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - GLH0314RVC (Ticagrelor)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Animals
MH  - Benzhydryl Compounds/*pharmacology
MH  - Diabetes Mellitus, Type 2/complications/*drug therapy/enzymology
MH  - Diabetic Cardiomyopathies/enzymology/etiology/physiopathology/*prevention & 
      control
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - Enzyme Activation
MH  - Fibrosis
MH  - Glucosides/*pharmacology
MH  - Inflammasomes/*metabolism
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 2/metabolism
MH  - Mice, Inbred C57BL
MH  - Myocytes, Cardiac/*drug effects/enzymology
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism
MH  - Purinergic P2Y Receptor Antagonists/*pharmacology
MH  - Signal Transduction
MH  - Sodium-Glucose Transporter 2 Inhibitors/*pharmacology
MH  - Stroke Volume/drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Ticagrelor/*pharmacology
MH  - Ventricular Function, Left/drug effects
MH  - Ventricular Remodeling/drug effects
OTO - NOTNLM
OT  - AMPK
OT  - Apoptosis
OT  - Cardiomyopathy
OT  - Dapagliflozin
OT  - Diabetes mellitus
OT  - Fibrosis
OT  - Inflammasome
OT  - Ticagrelor
OT  - mTOR
EDAT- 2020/04/27 06:00
MHDA- 2020/11/28 06:00
CRDT- 2020/04/27 06:00
PHST- 2020/04/27 06:00 [pubmed]
PHST- 2020/11/28 06:00 [medline]
PHST- 2020/04/27 06:00 [entrez]
AID - 10.1007/s10557-020-06978-y [pii]
AID - 10.1007/s10557-020-06978-y [doi]
PST - ppublish
SO  - Cardiovasc Drugs Ther. 2020 Aug;34(4):443-461. doi: 10.1007/s10557-020-06978-y.