Chronic metformin treatment decreases cardiac injury during ischemia-reperfusion by attenuating endoplasmic reticulum stress with improved mitochondrial function.
Chronic metformin treatment decreases cardiac injury during ischemia-reperfusion by attenuating endoplasmic reticulum stress with improved mitochondrial function.
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DOI：
10.18632/aging.202858
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发表时间：
2021-03-22
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影响因子：
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通讯作者：
Lesnefsky EJ
中科院分区：
文献类型：
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作者：
Chen Q;Thompson J;Hu Y;Lesnefsky EJ
衰老会损害线粒体功能，导致缺血和再灌注期间更大的心脏损伤。心脏内质网（ER）应激随着年龄的增长而增加，并导致线粒体功能障碍。二甲双胍是一种抗糖尿病药物，可在急性内质网应激期间保护心脏线粒体。我们假设二甲双胍治疗可以通过减轻内质网应激来改善老年心脏中先前存在的线粒体功能障碍，从而减少随后的缺血和再灌注期间的心脏损伤。雄性年轻小鼠（3 个月）和老年小鼠（24 个月）接受溶解在饮用水中的二甲双胍（300 毫克/公斤/天）和蔗糖（0.2 克/100 毫升）作为甜味剂，与单独的蔗糖载体相比，持续两周。分离细胞质、肌膜下线粒体（SSM）和原纤维间线粒体（IFM）。在不同的组中，使用 25 分钟的离体离体心脏灌注来评估心脏保护作用。全局缺血和 60 分钟。再灌注。测量梗塞面积。二甲双胍治疗24个月后，CHOP和裂解的ATF6含量降低。小鼠与媒介物相比，支持内质网应激的减少。二甲双胍治疗在 24 个月内改善了 IFM 的 OXPHOS。使用复合物 I 底物。二甲双胍治疗可减少缺血再灌注后的梗塞面积。因此，二甲双胍喂养通过抑制内质网应激改善缺血前线粒体功能，从而减少老年小鼠缺血再灌注期间的心脏损伤。
Aging impairs mitochondrial function that leads to greater cardiac injury during ischemia and reperfusion. Cardiac endoplasm reticulum (ER) stress increases with age and contributes to mitochondrial dysfunction. Metformin is an anti-diabetic drug that protects cardiac mitochondria during acute ER stress. We hypothesized that metformin treatment would improve preexisting mitochondrial dysfunction in aged hearts by attenuating ER stress, followed by a decrease in cardiac injury during subsequent ischemia and reperfusion. Male young (3 mo.) and aged mice (24 mo.) received metformin (300 mg/kg/day) dissolved in drinking water with sucrose (0.2 g/100 ml) as sweetener for two weeks versus sucrose vehicle alone. Cytosol, subsarcolemmal (SSM), and interfibrillar mitochondria (IFM) were isolated. In separate groups, cardioprotection was evaluated using ex vivo isolated heart perfusion with 25 min. global ischemia and 60 min. reperfusion. Infarct size was measured. The contents of CHOP and cleaved ATF6 were decreased in metformin-treated 24 mo. mice compared to vehicle, supporting a decrease in ER stress. Metformin treatment improved OXPHOS in IFM in 24 mo. using a complex I substrate. Metformin treatment decreased infarct size following ischemia-reperfusion. Thus, metformin feeding decreased cardiac injury in aged mice during ischemia-reperfusion by improving pre-ischemic mitochondrial function via inhibition of ER stress.