Hyperglycemia-Induced Oxidative Stress Abrogates Remifentanil Preconditioning-Mediated Cardioprotection in Diabetic Rats by Impairing Caveolin-3-Modulated PI3K/Akt and JAK2/STAT3 Signaling
Hyperglycemia-Induced Oxidative Stress Abrogates Remifentanil Preconditioning-Mediated Cardioprotection in Diabetic Rats by Impairing Caveolin-3-Modulated PI3K/Akt and JAK2/STAT3 Signaling
复制标题
高血糖诱导的氧化应激通过损害 Caveolin-3 调节的 PI3K/Akt 和 JAK2/STAT3 信号传导消除瑞芬太尼预处理介导的糖尿病大鼠心脏保护作用
DOI：
10.1155/2019/9836302
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发表时间：
2019-09-05
影响因子：
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通讯作者：
Irwin, Michael G.
中科院分区：
文献类型：
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作者：
Lei, Shaoqing;Su, Wating;Irwin, Michael G.
糖尿病心脏易受缺血/再灌注（I/R）损伤，对瑞芬太尼预处理（RPC）反应较低，但其机制尚不完全清楚。Caveolin-3（Cav-3）是心肌细胞小窝的主要亚型，在氧化应激增加的糖尿病心脏中减少。这项研究确定了糖尿病中受损的RPC是否是高血糖诱导的氧化应激的独立表现或与Cav-3表达受损相关的信号异常有关。RPC显着衰减缺血后梗死，心功能不全，心肌细胞凋亡，和15-F2 t-异前列腺素的生产（氧化应激的一个特定标志物），伴随着增加Cav-3的表达和增强Akt和STAT 3激活在控制，但不是在糖尿病大鼠。用抗氧化剂N-乙酰半胱氨酸（NAC）预处理可减弱高血糖诱导的Cav-3表达减少以及Akt和STAT 3激活，并恢复糖尿病中RPC介导的心脏保护作用，这种保护作用可通过AAV 9-shRNA-Cav-3、PI 3 K/Akt抑制剂渥曼青霉素或JAK 2/STAT 3抑制剂AG 490对Cav-3的心脏特异性敲低而被消除。类似地，NAC可以恢复RPC对高糖和缺氧/复氧诱导的损伤的保护作用，证据是LDH释放、15-F2 t-异前列烷、O2−和JC-1单体细胞水平降低，这些都可以被分离的原代心肌细胞中的小窝破坏剂甲基-β-环糊精、渥曼青霉素或AG 490或H9 C2细胞中Cav-3、Akt或STAT 3的siRNA逆转。甲基-β-环糊精或Cav-3敲低降低Akt和STAT 3活化。此外，通过选择性抑制剂或siRNA抑制Akt活化降低了STAT 3活化，反之亦然，但它们对Cav-3表达没有影响。因此，高血糖诱导的氧化应激通过损害Cav-3调节的PI 3 K/Akt和JAK 2/STAT 3信号传导来消除RPC心脏保护。NAC抗氧化治疗可通过改善Cav-3依赖的Akt和STAT 3激活以及促进PI 3 K/Akt和JAK 2/STAT 3信号通路之间的串扰来恢复RPC诱导的糖尿病心脏保护作用。
Diabetic hearts are more vulnerable to ischemia/reperfusion (I/R) injury and less responsive to remifentanil preconditioning (RPC), but the underlying mechanisms are incompletely understood. Caveolin-3 (Cav-3), the dominant isoform of cardiomyocyte caveolae, is reduced in diabetic hearts in which oxidative stress is increased. This study determined whether the compromised RPC in diabetes was an independent manifestation of hyperglycemia-induced oxidative stress or linked to impaired Cav-3 expression with associated signaling abnormality. RPC significantly attenuated postischemic infarction, cardiac dysfunction, myocardial apoptosis, and 15-F2t-isoprostane production (a specific marker of oxidative stress), accompanied with increased Cav-3 expression and enhanced Akt and STAT3 activation in control but not in diabetic rats. Pretreatment with the antioxidant N-acetylcysteine (NAC) attenuated hyperglycemia-induced reduction of Cav-3 expression and Akt and STAT3 activation and restored RPC-mediated cardioprotection in diabetes, which was abolished by cardiac-specific knockdown of Cav-3 by AAV9-shRNA-Cav-3, PI3K/Akt inhibitor wortmannin, or JAK2/STAT3 inhibitor AG490, respectively. Similarly, NAC could restore RPC protection from high glucose and hypoxia/reoxygenation-induced injury evidenced by decreased levels of LDH release, 15-F2t-isoprostane, O2−, and JC-1 monomeric cells, which were reversed by caveolae disrupter methyl-β-cyclodextrin, wortmannin, or AG490 in isolated primary cardiomyocytes or siRNAs of Cav-3, Akt, or STAT3 in H9C2 cells. Either methyl-β-cyclodextrin or Cav-3 knockdown reduced Akt and STAT3 activation. Further, the inhibition of Akt activation by a selective inhibitor or siRNA reduced STAT3 activation and vice versa, but they had no effects on Cav-3 expression. Thus, hyperglycemia-induced oxidative stress abrogates RPC cardioprotection by impairing Cav-3-modulated PI3K/Akt and JAK2/STAT3 signaling. Antioxidant treatment with NAC could restore RPC-induced cardioprotection in diabetes by improving Cav-3-dependent Akt and STAT3 activation and by facilitating the cross talk between PI3K/Akt and JAK2/STAT3 signaling pathways.