Sestrin2 Mediates Metformin Rescued the Age-Related Cardiac Dysfunctions of Cardiorenal Syndrome Type 3.
Sestrin2 Mediates Metformin Rescued the Age-Related Cardiac Dysfunctions of Cardiorenal Syndrome Type 3.
复制标题
作者：
Iglesias, Migdalia;Wang, Hao;Krause-Hauch, Meredith;Ren, Di;Zoungrana, Linda Ines;Li, Zehui;Zhang, Jie;Wei, Jin;Yadav, Nikita;Patel, Kshama;Fatmi, Mohammad Kasim;Liu, Ruisheng;Lesnefsky, Edward J.;Li, Ji
急性肾损伤（阿基）通过氧化应激（OS）导致心肾综合征3型（CRS 3）的急性心脏损伤和功能障碍。应激诱导的Sestrin 2（Sesn 2）蛋白减少活性氧（ROS）的积累并激活AMP依赖性蛋白激酶（AMPK）以调节OS期间的细胞代谢和能量。Sesn 2水平及其保护作用在老年心脏中下降。抗糖尿病药物二甲双胍上调Sesn 2水平以响应缺血-再灌注（IR）应激。然而，二甲双胍在CRS 3中的作用仍然未知。本研究旨在探索心脏Sesn 2水平的年龄相关性降低如何导致对AKI诱导的损伤的心脏不耐受，以及二甲双胍如何通过Sesn 2改善CRS 3。将年轻（3-5个月）和老年（21-23个月）C57 BL/6 J野生型小鼠沿着心肌细胞特异性敲除（cSesn 2 −/−）及其同窝野生型（Sesn 2f/f）C57 BL/6 J小鼠进行阿基15 min，然后再灌注24 h。通过超声心动图和海马线粒体呼吸分析评价心脏和线粒体功能。收集肾脏和心脏组织进行组织学分析和免疫印迹。结果表明，二甲双胍可通过改善年轻、Sesn 2f/f，尤其是老年小鼠的收缩和舒张功能、纤维化和细胞损伤以及线粒体功能，显著挽救AKI诱导的心功能障碍和损伤。二甲双胍显著增加老年左心室组织中阿基应激下Sesn 2的表达。因此，这项研究表明，Sesn 2介导了二甲双胍在AKI后的心脏保护作用。
Acute kidney injury (AKI) leads to acute cardiac injury and dysfunction in cardiorenal syndrome Type 3 (CRS3) through oxidative stress (OS). The stress-inducible Sestrin2 (Sesn2) protein reduces reactive oxygen species (ROS) accumulation and activates AMP-dependent protein kinase (AMPK) to regulate cellular metabolism and energetics during OS. Sesn2 levels and its protective effects decline in the aged heart. Antidiabetic drug metformin upregulates Sesn2 levels in response to ischemia–reperfusion (IR) stress. However, the role of metformin in CRS3 remains unknown. This study seeks to explore how the age-related decrease in cardiac Sesn2 levels contributes to cardiac intolerance to AKI-induced insults, and how metformin ameliorates CRS3 through Sesn2. Young (3–5 months) and aged (21–23 months) C57BL/6J wild-type mice along with cardiomyocyte-specific knockout (cSesn2−/−) and their wild type of littermate (Sesn2f/f) C57BL/6J mice were subjected to AKI for 15 min followed by 24 h of reperfusion. Cardiac and mitochondrial functions were evaluated through echocardiograms and seahorse mitochondria respirational analysis. Renal and cardiac tissue was collected for histological analysis and immunoblotting. The results indicate that metformin could significantly rescue AKI-induced cardiac dysfunction and injury via Sesn2 through an improvement in systolic and diastolic function, fibrotic and cellular damage, and mitochondrial function in young, Sesn2f/f, and especially aged mice. Metformin significantly increased Sesn2 expression under AKI stress in the aged left-ventricular tissue. Thus, this study suggests that Sesn2 mediates the cardioprotective effects of metformin during post-AKI.
登录
查看更多内容
DOI：
10.1016/b978-0-12-394309-5.00006-7
发表时间：
2012
影响因子：
--
作者：
Kalogeris, Theodore;Baines, Christopher P.;Krenz, Maike;Korthuis, Ronald J.
通讯作者：
Korthuis, Ronald J.
影响因子：
3.6
作者：
Talman, Virpi;Ruskoaho, Heikki
通讯作者：
Ruskoaho, Heikki
影响因子：
4.6
作者：
Orang A;Ali SR;Petersen J;McKinnon RA;Aloia AL;Michael MZ
通讯作者：
Michael MZ
影响因子：
3.8
作者：
Li, Xuan;Liu, Jia;Li, Ji
通讯作者：
Li, Ji
影响因子：
3.7
作者：
Hill BG;Benavides GA;Lancaster JR Jr;Ballinger S;Dell'Italia L;Jianhua Z;Darley-Usmar VM
通讯作者：
Darley-Usmar VM