BACKGROUND AMP-activated protein kinase (AMPK), particularly AMPKα2 isoform, plays a critical role in maintaining cardiac homeostasis. It was reported that sulforaphane (SFN) prevented type 2 diabetes (T2D)-induced cardiomyopathy accompanied by the activation of AMPK; In this study, AMPK's pivotal role in SFN-mediated prevention against T2D-induced cardiomyopathy was tested using global deletion of AMPKα2 gene (AMPKα2-KO) mice. METHODS AND RESULTS T2D was established by feeding 3-month high-fat diet (HFD) to induce insulin resistance, followed by an intraperitoneal injection of streptozotocin (STZ) to induce mild hyperglycemia in both AMPKα2-KO and wild-type (WT) mice. Then both T2D and control mice were subsequently treated with or without SFN for 3 months while continually feeding HFD or normal diet. Upon completion of the 3-month treatment, five mice from each group were sacrificed as a 3-month time-point (3 M). The rest continued normal diet or HFD until terminating study at the sixth month (6 M) of diabetes. Cardiac function was examined with echocardiography before sacrifice at both 3 M and 6 M. SFN prevented T2D-induced progression of cardiac dysfunction, remodeling (hypertrophy and fibrosis), inflammation, and oxidative damage in wild-type diabetic mice, but not in AMPKα2-KO mice. Mechanistically, SFN prevented T2D-induced cardiomyopathy not only by improving AMPK-mediated lipid metabolic pathways, but also enhancing NRF2 activation via AMPK/AKT/GSK3β pathway. However, these improving effects of SFN were abolished in AMPKα2-KO diabetic mice. CONCLUSIONS AMPK is indispensable for the SFN-induced prevention of cardiomyopathy in T2D, and the activation of NRF2 by SFN is mediated by AMPK/AKT/GSK3β signaling pathways.

中文翻译：

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萝卜硫烷通过AMPK介导的脂质代谢途径和NRF2功能的激活对2型糖尿病诱发的心肌病的保护作用。

背景技术AMP激活的蛋白激酶（AMPK），尤其是AMPKα2亚型，在维持心脏稳态方面起着关键作用。据报道，萝卜硫烷（SFN）预防了2型糖尿病（T2D）诱发的心肌病，并伴有AMPK的激活。在这项研究中，使用AMPKα2基因（AMPKα2-KO）的整体缺失来测试AMPK在SFN介导的预防T2D诱发的心肌病中的关键作用。方法和结果T2D的建立是通过喂养3个月的高脂饮食（HFD）诱导胰岛素抵抗，然后腹膜内注射链脲佐菌素（STZ）诱导AMPKα2-KO和野生型（WT）小鼠轻度高血糖。然后，在连续喂HFD或正常饮食的同时，对T2D和对照小鼠进行3个月的SFN或不SFN治疗。完成3个月的治疗后，将每个组的五只小鼠处死，作为3个月的时间点（3M）。其余的继续正常饮食或HFD，直到在糖尿病的第六个月（6M）终止研究。在3 M和6 M处处死之前，先用超声心动图检查心脏功能。SFN预防了T2D诱导的心功能障碍，野生型糖尿病小鼠的重塑（肥大和纤维化），炎症和氧化损伤进展，但不适用于AMPKα2- KO小鼠。从机制上讲，SFN不仅可以通过改善AMPK介导的脂质代谢途径来预防T2D诱发的心肌病，还可以通过AMPK / AKT /GSK3β途径增强NRF2激活。但是，在AMPKα2-KO糖尿病小鼠中，SFN的这些改善作用已被消除。结论AMPK对于SFN诱导的T2D心肌病的预防是必不可少的，