Dapagliflozin improves left ventricular remodeling and aorta sympathetic tone in a pig model of heart failure with preserved ejection fraction
Dapagliflozin improves left ventricular remodeling and aorta sympathetic tone in a pig model of heart failure with preserved ejection fraction
复制标题
达格列净改善射血分数保留的心力衰竭猪模型的左心室重构和主动脉交感张力
DOI：
10.1186/s12933-019-0914-1
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发表时间：
2019-08-20
影响因子：
9.3
通讯作者：
Zhou, Yafeng
中科院分区：
文献类型：
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作者：
Zhang, Nannan;Feng, Bin;Zhou, Yafeng
研究背景射血分数保留的心力衰竭（HFpEF）是一种发病率和死亡率较高的疑难疾病，缺乏有效的治疗方法。在此，我们报告了钠-葡萄糖协同转运蛋白 2 抑制剂 (SGLT2i) 达格列净对高血压+高脂血症诱导的 HFpEF 猪模型的治疗效果。方法通过注射醋酸脱氧皮质酮 (DOCA) 和血管紧张素 II (Ang II) 组合并采用西式饮食 (WD) 喂养 18 周来建立 HFpEF 猪。在第 9 周，一半的 HFpEF 猪被随机分配接受额外的达格列净治疗（10 毫克/天），在接下来的 9 周内每天口服强饲法。测量血压、血脂水平、超声心动图和心脏血流动力学的心脏结构和功能变化，以及血浆和组织中的肾上腺素和去甲肾上腺素浓度。处死后，还测定了心脏纤维化、心血管系统中酪氨酸羟化酶（TH）、炎症因子（IL-6和TNF-α）的分布以及NO-cGMP-PKG通路活性。结果达格列净治疗9周后，HFpEF猪的血压、总胆固醇（TC）、甘油三酯（TG）和低密度脂蛋白（LDL）显着升高，但仅血压显着下降。通过超声心动图和血流动力学评估，达格列净显着减弱 HFpEF 猪的心脏同心重塑，但未能改善舒张功能和左心室 (LV) 顺应性。在达格列净治疗组中，与 HFpEF 组相比，主动脉中的 TH 表达和去甲肾上腺素浓度明显减轻。此外，HFpEF猪主动脉组织中的炎症细胞因子如IL-6和TNF-α显着升高，并被达格列净抑制。此外，HFpEF猪主动脉中减少的eNOS和PKG-1蛋白表达以及cGMP含量在达格列净治疗9周后显着恢复。结论达格列净治疗9周可降低HFpEF猪的高血压并逆转左心室同心重塑，部分原因是抑制主动脉交感神经张力，从而抑制炎症反应和NO-cGMP-PKG通路激活。
BackgroundHeart failure with preserved ejection fraction (HFpEF) is a difficult disease with high morbidity and mortality rates and lacks an effective treatment. Here, we report the therapeutic effect of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), on hypertension + hyperlipidemia-induced HFpEF in a pig model.MethodsHFpEF pigs were established by infusing a combination of deoxycorticosterone acetate (DOCA) and angiotensin II (Ang II), and Western diet (WD) feeding for 18 weeks. In the 9th week, half of the HFpEF pigs were randomly assigned to receive additional dapagliflozin treatment (10 mg/day) by oral gavage daily for the next 9 weeks. Blood pressure, lipid levels, echocardiography and cardiac hemodynamics for cardiac structural and functional changes, as well as epinephrine and norepinephrine concentrations in the plasma and tissues were measured. After sacrifice, cardiac fibrosis, the distribution of tyrosine hydroxylase (TH), inflammatory factors (IL-6 and TNF-α) and NO-cGMP-PKG pathway activity in the cardiovascular system were also determined.ResultsBlood pressure, total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) were markedly increased in HFpEF pigs, but only blood pressure was significantly decreased after 9 weeks of dapagliflozin treatment. By echocardiographic and hemodynamic assessment, dapagliflozin significantly attenuated heart concentric remodeling in HFpEF pigs, but failed to improve diastolic function and compliance with the left ventricle (LV). In the dapagliflozin treatment group, TH expression and norepinephrine concentration in the aorta were strongly mitigated compared to that in the HFpEF group. Moreover, inflammatory cytokines such as IL-6 and TNF-α in aortic tissue were markedly elevated in HFpEF pigs and inhibited by dapagliflozin. Furthermore, the reduced expression of eNOS and the PKG-1 protein and the cGMP content in the aortas of HFpEF pigs were significantly restored after 9 weeks of dapagliflozin treatment.Conclusion9 weeks of dapagliflozin treatment decreases hypertension and reverses LV concentric remodeling in HFpEF pigs partly by restraining sympathetic tone in the aorta, leading to inhibition of the inflammatory response and NO-cGMP-PKG pathway activation.