Ye Yumei, Bajaj Mandeep, Yang Hsiu-Chiung, Perez-Polo Jose R, Birnbaum Yochai
The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
The Section of Endocrinology, The Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Cardiovasc Drugs Ther. 2017 Apr;31(2):119-132. doi: 10.1007/s10557-017-6725-2.
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.
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.
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.
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.
我们评估了（1）达格列净（Dapa，一种SGLT2抑制剂）是否能减轻糖尿病小鼠心脏功能恶化、Nlrp3和炎性小体激活。（2）二肽基肽酶4抑制剂沙格列汀（Saxa）是否能增强这些作用。（3）达格列净对体外心肌成纤维细胞的作用可能不依赖于SGLT2。
2型糖尿病（BTBR ob/ob）小鼠和野生型（WT）小鼠接受溶剂、达格列净或达格列净+沙格列汀治疗8周。进行葡萄糖耐量试验和超声心动图检查。将WT和BTBR心脏的心肌成纤维细胞与达格列净一起孵育，并暴露于脂多糖。
WT小鼠的左心室射血分数（LVEF）为81±1%，2型糖尿病对照小鼠为53±1%。达格列净和达格列净+沙格列汀使BTBR小鼠的LVEF分别提高到68±1%和74.6±1%（p<0.001）。与WT心脏相比，BTBR心脏中NALP3、ASC、IL-1β、IL-6、半胱天冬酶-1和TNFα的mRNA水平显著更高；达格列净和达格列净+沙格列汀显著降低了这些水平。同样，与WT心脏相比，BTBR心脏中NLRP3、TNFα和半胱天冬酶-1的蛋白水平更高，并在达格列净作用下降低，达格列净+沙格列汀在更大程度上减轻了BTBR小鼠的升高。BTBR小鼠中胶原蛋白-1和胶原蛋白-3的mRNA水平显著升高，达格列净和达格列净+沙格列汀减轻了这些升高。BTBR小鼠中P-AMPK/总AMPK比值显著低于WT小鼠。达格列净和达格列净+沙格列汀同样提高了BTBR小鼠中的该比值。这项体外研究表明，BTBR心肌成纤维细胞中NALP3、ASC、IL-1β和半胱天冬酶-1的mRNA水平更高，达格列净可使其降低。该作用依赖于AMPK且不依赖于SGLT1。
达格列净减轻了BTBR小鼠炎性小体的激活、纤维化和LVEF的恶化。抗炎、抗纤维化作用可能不依赖于SGLT2和降糖作用，因为它们在体外模型中得到了验证。当在达格列净中加入沙格列汀时，对心脏重塑的作用增强。然而，在达格列净中加入沙格列汀对心肌纤维化和胶原蛋白水平的影响并未更大。
