Huan Chen1,2, Da Tran3, Hsiu-Chiung Yang4, Sven Nylander4, Yochai Birnbaum5, Yumei Ye6. 1. The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, BSB 648, Galveston, TX, 77555, USA. 2. Department of Acupuncture, First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 3. School of Medicine, University of Texas Medical Branch, Galveston, TX, USA. 4. Biopharmaceutical R&D, AstraZeneca, Gothenburg, Sweden. 5. The Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA. 6. The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, BSB 648, Galveston, TX, 77555, USA. yumye@utmb.edu.
Abstract
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 factorα (TNFα) 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.
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 factorα (TNFα) 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 BTBRmice with additive effects of the combination. While both dapagliflozin and ticagrelor activated AMPK, only dapagliflozin activated mTOR complex 2 (mTORC2) in hearts of BTBRmice.
Authors: Felipe Muñoz-Córdova; Carolina Hernández-Fuentes; Camila Lopez-Crisosto; Mayarling F Troncoso; Ximena Calle; Alejandra Guerrero-Moncayo; Luigi Gabrielli; Mario Chiong; Pablo F Castro; Sergio Lavandero Journal: Front Cardiovasc Med Date: 2021-12-23
Authors: Hubert Kolb; Kerstin Kempf; Martin Röhling; Martina Lenzen-Schulte; Nanette C Schloot; Stephan Martin Journal: BMC Med Date: 2021-12-09 Impact factor: 8.775