达帕格列净通过 AMPK-PINK1/Parkin 信号通路激活有丝分裂，从而缓解心肌缺血再灌注损伤

IF 2.8 3区医学 Q2 PERIPHERAL VASCULAR DISEASE

Current vascular pharmacology Pub Date : 2023-12-23 DOI:10.2174/0115701611269801231211104905

Wei Zuo, Liang Wang, Ran Tian, Lun Wang, Yifan Liu, Hao Qian, Xinglin Yang, Zhenyu Liu

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引用次数: 0

摘要

导言心肌缺血再灌注损伤（MIRI）决定了急性心肌梗死（AMI）后的梗死面积和长期预后。钠-葡萄糖共转运体 2 抑制剂达帕格列酮可减轻动物模型中的 MIRI。方法：我们研究了达帕格列净对 MIRI 的心脏保护作用的潜在机制，重点是线粒体损伤和有丝分裂。建立了 MIRI 小鼠和 H9C2 细胞模型。结果2,3,5-三苯基氯化四氮唑（TTC）染色显示，与模型组相比，预处理达帕格列净后 MIRI 明显减轻（14.91±1.76 vs. 40.47±3.69%）。治疗前达帕格列净组的数据显示，左室射血分数（LVEF）显著下降（44.8±2.7 vs. 28.5±5.3%，P<0.01）、左室舒张末期容积（LVEDV）（70.6±9.5 vs. 93.5±13.8 ul，P<0.05）和左室收缩末期容积（LVESV）（39.0±8.3 vs. 67.9±13.7 ul，P<0.05）与模型组相比均显著下降。达帕格列净还降低了活性氧（ROS）和线粒体DNA碎片的水平，逆转了线粒体膜电位的下降，抑制了细胞凋亡。进一步的研究表明，达帕格列净可以保护线粒体免受损伤，因为它可以通过磷酸酶和天丝同源物（PTEN）诱导的假定激酶1（PINK1）/park依赖性方式，通过线粒体吞噬迅速清除受损的线粒体。达帕格列净通过抑制 5'单磷酸腺苷激活的蛋白激酶（AMPK）-PINK1/parkin 信号通路来调节心肌细胞的有丝分裂，从而导致 MIRI 的减弱。结论达帕格列净通过AMPK-PINK1/parkin信号通路激活有丝分裂，从而缓解了MIRI。

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Dapagliflozin Alleviates Myocardial Ischaemia Reperfusion Injury by Activating Mitophagy via the AMPK-PINK1/Parkin Signalling Pathway

Introduction:: Myocardial ischaemia reperfusion injury (MIRI) determines infarct size and long-term outcomes after acute myocardial infarction (AMI). Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, alleviates MIRI in animal models. Method:: We investigated the potential mechanisms underlying the cardioprotective effect of dapagliflozin against MIRI, focusing on mitochondrial injury and mitophagy. MIRI mouse and H9C2 cell models were established. Results:: 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed a significant alleviation of MIRI after pre-treatment of dapagliflozin compared to the model group (14.91±1.76 vs. 40.47±3.69%). Data from the pre-treatment dapagliflozin group showed a significant decrease in left ventricular ejection fraction (LVEF) (44.8±2.7 vs. 28.5±5.3%, P<0.01), left ventricular end-diastolic volume (LVEDV) (70.6±9.5 vs. 93.5±13.8 ul, P<0.05), and left ventricular end-systolic volume (LVESV) (39.0± 8.3 vs. 67.9±13.7 ul, P<0.05) compared to the model group. Dapagliflozin also reduced the levels of reactive oxygen species (ROS) and fragmented mitochondrial DNA, reversed the decrease in mitochondrial membrane potential, and suppressed apoptosis. Further study showed that dapagliflozin could protect against mitochondrial injury by rapidly clearing damaged mitochondria via mitophagy in a phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1)/parkindependent manner. Dapagliflozin regulated mitophagy in cardiomyocytes by suppressing the adenosine 5’monophosphate-activated protein kinase (AMPK)-PINK1/parkin signalling pathway, resulting in attenuated MIRI. Conclusion:: Dapagliflozin alleviated MIRI by activating mitophagy via the AMPK-PINK1/parkin signalling pathway.

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来源期刊

Current vascular pharmacology 医学-外周血管病

CiteScore

9.20

自引率

4.40%

发文量

审稿时长

6-12 weeks

期刊介绍： Current Vascular Pharmacology publishes clinical and research-based reviews/mini-reviews, original research articles, letters, debates, drug clinical trial studies and guest edited issues to update all those concerned with the treatment of vascular disease, bridging the gap between clinical practice and ongoing research. Vascular disease is the commonest cause of death in Westernized countries and its incidence is on the increase in developing countries. It follows that considerable research is directed at establishing effective treatment for acute vascular events. Long-term treatment has also received considerable attention (e.g. for symptomatic relief). Furthermore, effective prevention, whether primary or secondary, is backed by the findings of several landmark trials. Vascular disease is a complex field with primary care physicians and nurse practitioners as well as several specialties involved. The latter include cardiology, vascular and cardio thoracic surgery, general medicine, radiology, clinical pharmacology and neurology (stroke units).