Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts
Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts
复制标题
DOI：
10.1016/j.metabol.2021.154936
复制
发表时间：
2021-11-20
影响因子：
9.8
通讯作者：
Paolisso, Giuseppe
中科院分区：
文献类型：
--
作者：
Marfella, Raffaele;D'Onofrio, Nunzia;Paolisso, Giuseppe
背景：实验性糖尿病心肌病的发病机制可能与激活蛋白1（AP-1）成员JunD有关。在糖尿病受者中使用非糖尿病心脏移植（HTX），我们检查了糖尿病环境（高血糖和胰岛素抵抗）对心脏JunD表达的影响超过12个月。由于钠/葡萄糖协同转运蛋白-2抑制剂（SGLT 2 i）可显著逆转近端肾小管细胞中高糖诱导的AP-1结合，因此我们研究了接受SGLT 2 i治疗的2型糖尿病受者亚组中的JunD表达。方法：我们评估了77例首次HTX接受者（分别为40例和37例糖尿病患者）。在糖尿病受者中，17例（45.9%）接受SGLT 2 i治疗。HTX接受者接受标准临床评估（代谢状态、超声心动图、冠状动脉计算机断层扫描血管造影和肌内膜活检）。在活检样本中，我们使用实时聚合酶链反应和免疫荧光法评估了JunD、胰岛素受体底物1和2（IRS 1和IRS 2）、过氧化物酶体增殖物激活受体-γ（PPAR-gamma）和神经酰胺水平。本研究中的活检评价在HTX后1-4周（基础）、5-12周（中期）和长达48周（最终，12个月随访结束）进行。结果如下：在患有糖尿病的受者中，JunD/PPAR-gamma和神经酰胺水平的心脏表达存在显著的早期和进行性增加，沿着IRS 1和IRS 2的显著降低，但在那些没有糖尿病的受者中没有。在接受SGLT 2 i治疗的糖尿病患者中，这些分子变化减弱。结论：人类糖尿病心肌病的早期发病机制与糖尿病患者HTX后JunD/PPAR-gamma过表达和脂质蓄积有关值得注意的是，与SGLT 2 i合并治疗可减少这种现象，SGLT 2 i直接作用于糖尿病心脏。(c)2021作者（S）爱思唯尔公司出版这是一个在CC BY-NC-ND许可证下的开放获取文章（http：//creativecommons.org/licenses/by-nc-nd/4.0/）。
Background: The pathogenesis of experimental diabetic cardiomyopathy may involve the activator protein 1 (AP-1) member, JunD. Using non-diabetic heart transplant (HTX) in recipients with diabetes, we examined the effects of the diabetic milieu (hyperglycemia and insulin resistance) on cardiac JunD expression over 12 months. Because so-dium/glucose cotransporter-2 inhibitors (SGLT2i) significantly reverse high glucose-induced AP-1 binding in the proximal tubular cell, we investigated JunD expression in a subgroup of type 2 diabetic recipients receiving SGLT2i treatment. Methods: We evaluated 77 first HTX recipients (40 and 37 patients with and without diabetes, respectively). Among the recipients with diabetes, 17 (45.9%) were receiving SGLT2i treatment. HTX recipients underwent standard clin-ical evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsy). In the biopsy samples, we evaluated JunD, insulin receptor substrates 1 and 2 (IRS1 and IRS2), peroxisome proliferator-activated receptor-gamma (PPAR-gamma), and ceramide levels using real-time polymerase chain reaction and immunofluorescence. The biopsy evaluations in this study were performed at 1-4 weeks (basal), 5-12 weeks (intermediate), and up to 48 weeks (final, end of 12-month follow-up) after HTX. Results: There was a significant early and progressive increase in the cardiac expression of JunD/PPAR-gamma and cer -amide levels, along with a significant decrease in IRS1 and IRS2 in recipients with diabetes but not in those without diabetes. These molecular changes were blunted in patients with diabetes receiving SGLT2i treatment. Conclusion: Early pathogenesis in human diabetic cardiomyopathy is associated with JunD/PPAR-gamma overexpression and lipid accumulation following HTX in recipients with diabetes. Remarkably, this phenomenon was reduced by concomitant therapy with SGLT2i, which acted directly on diabetic hearts. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).