Decreased PGC-1α Post-Cardiopulmonary Bypass Leads to Impaired Oxidative Stress in Diabetic Patients
Decreased PGC-1α Post-Cardiopulmonary Bypass Leads to Impaired Oxidative Stress in Diabetic Patients
复制标题
DOI：
10.1016/j.athoracsur.2018.08.009
复制
发表时间：
2019-02-01
影响因子：
4.6
通讯作者：
Matyal, Robina
中科院分区：
文献类型：
--
作者：
Mahmood, Eitezaz;Jeganathan, Jelliffe;Matyal, Robina
背景。糖尿病患者体外循环（CPB）术后线粒体功能障碍的机制尚不清楚。我们假设，在心脏手术后的患者中，脂肪酸的β -氧化受损导致应激反应恶化。经机构审查委员会批准，采集35例糖尿病患者和33例非糖尿病患者在CPB前后的右心房组织样本。糖化血红蛋白6.0及以上且临床诊断为糖尿病的患者被认为是糖尿病。免疫印迹和微阵列分析评估蛋白和基因表达的变化。用ImageJ对印迹进行量化，并在归一化后使用多重Student’st检验比较进行单向方差分析。p值小于0.05均认为显著。采用免疫组织化学方法对细胞脂质沉积进行评估。与非糖尿病患者相比，糖尿病患者CPB前后PGC-1 α水平明显降低（p < 0.01）。非糖尿病患者CPB前PGC-1 α的几个上游调节因子（SIRT1和CREB）显著升高（p分别= 0.01和0.0018）。CPB后糖尿病患者抗氧化标志物（NOX4、GPX4）、血管生成因子（tgf - β、NT3、Ang1）、抗凋亡因子BCL-xL均显著降低（p < 0.05）。糖尿病患者CPB后，支持线粒体能量产生的基因CREB5、SLC25A40和血管生成基因的表达显著下调（p < 0.05）。免疫组化结果显示糖尿病心肌组织脂质沉积明显增加。糖尿病患者PGC-1 α降低可能导致CPB后线粒体功能受损，抗凋亡和血管生成反应减弱。因此，PGC-1 α和上游调节因子可作为改善糖尿病患者β -氧化的靶点。(C) 2019年由胸外科学会主办
Background. The mechanism of mitochondrial dysfunction after cardiopulmonary bypass (CPB) in patients with diabetes mellitus lacks understanding. We hypothesized that impaired beta-oxidation of fatty acids leads to worsened stress response in this patient population after cardiac surgery.Methods. After Institutional Review Board approval, right atrial tissue samples were collected from 35 diabetic patients and 33 nondiabetic patients before and after CPB. Patients with glycated hemoglobin of 6.0 or greater and a clinical diagnosis of diabetes mellitus were considered to be diabetic. Immunoblotting and microarray analysis were performed to assess protein and gene expression changes. Blots were quantified with ImageJ and analyzed using one-way analysis of variance with multiple Student's t test comparisons after normalization. All p values less than 0.05 were considered significant. Immunohistochemistry was performed for cellular lipid deposition assessment.Results. Diabetic patients had significantly lower levels of PGC-1 alpha before and after CPB (p < 0.01 for both) compared with nondiabetic patients. Several upstream regulators of PGC-1 alpha (SIRT1 and CREB) were significantly higher in nondiabetic patients before CPB (p = 0.01 and 0.0018, respectively). Antioxidant markers (NOX4 and GPX4), angiogenic factors (TGF-beta, NT3, and Ang1), and the antiapoptotic factor BCL-xL were significantly lower in diabetic patients after CPB (p < 0.05). The expression of genes supporting mitochondrial energy production (CREB5 and SLC25A40) and angiogenic genes (p < 0.05) was significantly downregulated in diabetic patients after CPB. Immunohistochemistry results showed significantly increased lipid deposition in diabetic myocardial tissue.Conclusions. Decreased PGC-1 alpha in diabetic patients may lead to impaired mitochondrial function and attenuated antiapoptotic and angiogenic responses after CPB. Therefore, PGC-1 alpha and upstream regulators could serve as a target for improving beta-oxidation in diabetic patients. (C) 2019 by The Society of Thoracic Surgeons