Pioglitazone Inhibits Diabetes-Induced Atrial Mitochondrial Oxidative Stress and Improves Mitochondrial Biogenesis, Dynamics, and Function Through the PPAR-γ/PGC-1α Signaling Pathway.
Pioglitazone Inhibits Diabetes-Induced Atrial Mitochondrial Oxidative Stress and Improves Mitochondrial Biogenesis, Dynamics, and Function Through the PPAR-γ/PGC-1α Signaling Pathway.
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DOI：
10.3389/fphar.2021.658362
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发表时间：
2021
影响因子：
5.6
通讯作者：
Liu T
中科院分区：
文献类型：
--
作者：
Zhang Z;Zhang X;Meng L;Gong M;Li J;Shi W;Qiu J;Yang Y;Zhao J;Suo Y;Liang X;Wang X;Tse G;Jiang N;Li G;Zhao Y;Liu T
背景：氧化应激导致糖尿病的不良心房重塑。 PPAR-γ 激动剂吡格列酮可以通过其抗氧化和抗炎作用来阻止这种重塑。在这项研究中，我们研究了吡格列酮对糖尿病兔模型心房重构的保护作用的分子机制。 方法：将家兔随机分为对照组、糖尿病组和吡格列酮治疗糖尿病组。测量超声心动图、血流动力学和电生理学参数。测量血清 PPAR-γ 水平、血清和组织氧化应激和炎症标志物、线粒体形态、活性氧 (ROS) 产生率、呼吸功能和线粒体膜电位 (MMP) 水平。测量了促纤维化标记物 TGF-β1、PPAR-γ 辅激活因子-1α (PGC-1α) 和线粒体蛋白（生物发生、融合和裂变相关蛋白）的蛋白表达。用 PGC-1α 小干扰 RNA (siRNA) 转染 HL-1 细胞，以确定吡格列酮改善氧化应激下线粒体功能的潜在机制。 结果：糖尿病组的左心房直径和纤维化面积比对照组更大，这与诱发性心房颤动（AF）的发生率更高有关。较低的血清 PPAR-γ 水平与较低的 PGC-1α 以及较高的 NF-κB 和 TGF-β1 表达相关。检测到较低的线粒体生物合成（PGC-1α、NRF1 和 TFAM）、融合（Opa1 和 Mfn1）和裂变（Drp1）相关蛋白。观察到线粒体肿胀、线粒体 ROS 升高、呼吸控制率降低和 MMP 降低。吡格列酮组表现出结构重塑的逆转和诱导性房颤发生率较低，这与较高的 PPAR-γ 和 PGC-1α 相关。吡格列酮组的 NF-κB 和 TGF-β1 表达水平较低，而生物发生、融合和裂变相关蛋白表达水平较高。此外，线粒体的结构和功能得到改善。在 HL-1 细胞中，PGC-1α siRNA 转染减弱了吡格列酮对 H2O2 处理的细胞中 Mn-SOD 蛋白表达和 MMP 崩溃的影响。 结论：糖尿病可引起不良心房结构、电生理重塑以及线粒体损伤和功能障碍。吡格列酮通过 PPAR-γ/PGC-1α 途径预防这些异常。
Background: Oxidative stress contributes to adverse atrial remodeling in diabetes mellitus. This remodeling can be prevented by the PPAR-γ agonist pioglitazone via its antioxidant and anti-inflammatory effects. In this study, we examined the molecular mechanisms underlying the protective effects of pioglitazone on atrial remodeling in a rabbit model of diabetes. Methods: Rabbits were randomly divided into control, diabetic, and pioglitazone-treated diabetic groups. Echocardiographic, hemodynamic, and electrophysiological parameters were measured. Serum PPAR-γ levels, serum and tissue oxidative stress and inflammatory markers, mitochondrial morphology, reactive oxygen species (ROS) production rate, respiratory function, and mitochondrial membrane potential (MMP) levels were measured. Protein expression of the pro-fibrotic marker TGF-β1, the PPAR-γ coactivator-1α (PGC-1α), and the mitochondrial proteins (biogenesis-, fusion-, and fission-related proteins) was measured. HL-1 cells were transfected with PGC-1α small interfering RNA (siRNA) to determine the underlying mechanisms of pioglitazone improvement of mitochondrial function under oxidative stress. Results: The diabetic group demonstrated a larger left atrial diameter and fibrosis area than the controls, which were associated with a higher incidence of inducible atrial fibrillation (AF). The lower serum PPAR-γ level was associated with lower PGC-1α and higher NF-κB and TGF-β1 expression. Lower mitochondrial biogenesis (PGC-1α, NRF1, and TFAM)-, fusion (Opa1 and Mfn1)-, and fission (Drp1)-related proteins were detected. Mitochondrial swelling, higher mitochondrial ROS, lower respiratory control rate, and lower MMP were observed. The pioglitazone group showed a reversal of structural remodeling and a lower incidence of inducible AF, which were associated with higher PPAR-γ and PGC-1α. The pioglitazone group had lower NF-κB and TGF-β1 expression levels, whereas biogenesis-, fusion-, and fission-related protein expression was higher. Further, mitochondrial structure and function were improved. In HL-1 cells, PGC-1α siRNA transfection blunted the effect of pioglitazone on Mn-SOD protein expression and MMP collapse in H2O2-treated cells. Conclusion: Diabetes mellitus induces adverse atrial structural, electrophysiological remodeling, and mitochondrial damage and dysfunction. Pioglitazone prevented these abnormalities through the PPAR-γ/PGC-1α pathway.
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影响因子：
2.4
作者：
DeFronzo, Ralph A.;Inzucchi, Silvio;Nissen, Steven E.
通讯作者：
Nissen, Steven E.
影响因子：
168.9
作者：
Dormandy, JA;Charbonnel, B;Taton, J
通讯作者：
Taton, J
影响因子：
5
作者：
Gu, Jun;Liu, Xu;Zhang, Da-Dong
通讯作者：
Zhang, Da-Dong
影响因子：
37.8
作者：
Chugh SS;Havmoeller R;Narayanan K;Singh D;Rienstra M;Benjamin EJ;Gillum RF;Kim YH;McAnulty JH Jr;Zheng ZJ;Forouzanfar MH;Naghavi M;Mensah GA;Ezzati M;Murray CJ
通讯作者：
Murray CJ
吡格列酮可减轻四氧嘧啶诱发的糖尿病兔的心房重塑和房颤易感性
影响因子：
3.1
作者：
Liu, Changle;Liu, Ruimeng;Liu, Tong
通讯作者：
Liu, Tong