达格列净和替格瑞洛对 NLRP3 炎性小体激活和糖尿病心肌病进展的抑制作用具有相加效应：AMPK-mTOR 相互作用。

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.

机构信息

The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, BSB 648, Galveston, TX, 77555, USA.

Department of Acupuncture, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

出版信息

Cardiovasc Drugs Ther. 2020 Aug;34(4):443-461. doi: 10.1007/s10557-020-06978-y.

DOI:10.1007/s10557-020-06978-y

PMID:32335797

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.

摘要

目的

替格瑞洛是一种 P2Y12 受体拮抗剂，达格列净是一种钠-葡萄糖共转运蛋白 2 抑制剂，均可抑制 NLRP3 炎性小体的激活。达格列净的抗炎作用依赖于 AMPK 的激活，而替格瑞洛也可以激活 AMPK。我们评估了达格列净和替格瑞洛联合应用是否对 2 型糖尿病小鼠糖尿病心肌病的进展有叠加作用。

方法

8 周龄 BTBR 和野生型小鼠分别给予无药物、达格列净（1.5mg/kg/天）、替格瑞洛（100mg/kg/天）或二者联合治疗 12 周。通过超声心动图评估心功能，并用心脏组织样本评估纤维化、细胞凋亡、qRT-PCR 和免疫印迹。

结果

两种药物均能减轻糖尿病心肌病的进展，表现为左心室收缩末期和舒张末期容积及左心室射血分数的改善，联合应用可进一步改善。两种药物均能减轻 NOD 样受体 3（NLRP3）炎性小体和纤维化的激活。联合用药的效果明显优于单独用药，表现为心肌组织坏死因子α（TNFα）和白细胞介素-6（IL-6）水平的降低，提示存在叠加作用。联合用药对 ASC、胶原-1 和胶原-3mRNA 水平的作用也大于单独用药。虽然两种药物均能激活腺苷单磷酸激酶（AMPK），但只有达格列净能激活 mTOR 并增加 RICTOR 水平。此外，只有达格列净能降低心肌 BNP 和 Caspase-1mRNA 水平，达格列净对 NLRP3 和胶原-3mRNA 水平的作用明显大于替格瑞洛。