Yu Li-Ming, Dong Xue, Xue Xiao-Dong, Xu Shu, Zhang Xu, Xu Yin-Li, Wang Zhi-Shang, Wang Yang, Gao Hao, Liang Yan-Xiao, Yang Yang, Wang Hui-Shan
Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, China.
Outpatient Department of Liaoning Military Region, General Hospital of Northern Theater Command, Shenyang, China.
J Pineal Res. 2021 Jan;70(1):e12698. doi: 10.1111/jpi.12698. Epub 2020 Oct 24.
Targeting mitochondrial quality control with melatonin has been found promising for attenuating diabetic cardiomyopathy (DCM), although the underlying mechanisms remain largely undefined. Activation of SIRT6 and melatonin membrane receptors exerts cardioprotective effects while little is known about their roles during DCM. Using high-fat diet-streptozotocin-induced diabetic rat model, we found that prolonged diabetes significantly decreased nocturnal circulatory melatonin and heart melatonin levels, reduced the expressions of cardiac melatonin membrane receptors, and decreased myocardial SIRT6 and AMPK-PGC-1α-AKT signaling. 16 weeks of melatonin treatment inhibited the progression of DCM and the following myocardial ischemia-reperfusion (MI/R) injury by reducing mitochondrial fission, enhancing mitochondrial biogenesis and mitophagy via re-activating SIRT6 and AMPK-PGC-1α-AKT signaling. After the induction of diabetes, adeno-associated virus carrying SIRT6-specific small hairpin RNA or luzindole was delivered to the animals. We showed that SIRT6 knockdown or antagonizing melatonin receptors abolished the protective effects of melatonin against mitochondrial dysfunction as evidenced by aggravated mitochondrial fission and reduced mitochondrial biogenesis and mitophagy. Additionally, SIRT6 shRNA or luzindole inhibited melatonin-induced AMPK-PGC-1α-AKT activation as well as its cardioprotective actions. Collectively, we demonstrated that long-term melatonin treatment attenuated the progression of DCM and reduced myocardial vulnerability to MI/R injury through preserving mitochondrial quality control. Melatonin membrane receptor-mediated SIRT6-AMPK-PGC-1α-AKT axis played a key role in this process. Targeting SIRT6 with melatonin treatment may be a promising strategy for attenuating DCM and reducing myocardial vulnerability to ischemia-reperfusion injury in diabetic patients.
尽管潜在机制仍不清楚，但以褪黑素靶向线粒体质量控制已被发现有望减轻糖尿病性心肌病（DCM）。SIRT6和褪黑素膜受体的激活发挥心脏保护作用，而它们在DCM期间的作用却知之甚少。使用高脂饮食-链脲佐菌素诱导的糖尿病大鼠模型，我们发现长期糖尿病显著降低夜间循环褪黑素和心脏褪黑素水平，降低心脏褪黑素膜受体的表达，并降低心肌SIRT6和AMPK-PGC-1α-AKT信号通路。16周的褪黑素治疗通过重新激活SIRT6和AMPK-PGC-1α-AKT信号通路，减少线粒体分裂，增强线粒体生物发生和线粒体自噬，从而抑制DCM的进展以及随后的心肌缺血再灌注（MI/R）损伤。在诱导糖尿病后，将携带SIRT6特异性小发夹RNA或鲁辛朵的腺相关病毒注射到动物体内。我们发现，SIRT6基因敲低或拮抗褪黑素受体会消除褪黑素对线粒体功能障碍的保护作用，这表现为线粒体分裂加剧、线粒体生物发生和线粒体自噬减少。此外，SIRT6 shRNA或鲁辛朵抑制褪黑素诱导的AMPK-PGC-1α-AKT激活及其心脏保护作用。总的来说，我们证明长期褪黑素治疗通过维持线粒体质量控制减轻了DCM的进展，并降低了心肌对MI/R损伤的易感性。褪黑素膜受体介导的SIRT6-AMPK-PGC-1α-AKT轴在此过程中起关键作用。用褪黑素治疗靶向SIRT6可能是减轻糖尿病患者DCM和降低心肌对缺血再灌注损伤易感性的一种有前景的策略。
