Pyridostigmine alleviates cardiac dysfunction via improving mitochondrial cristae shape in a mouse model of metabolic syndrome.
Pyridostigmine alleviates cardiac dysfunction via improving mitochondrial cristae shape in a mouse model of metabolic syndrome.
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吡啶斯的明通过改善代谢综合征小鼠模型中的线粒体嵴形状来减轻心脏功能障碍。
DOI：
10.1016/j.freeradbiomed.2019.01.011
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发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
Zang Wei-Jin
中科院分区：
文献类型：
--
作者：
Xue Run-Qing;Yu Xiao-Jiang;Zhao Ming;Xu Man;Wu Qing;Cui Yan-Ling;Yang Si;Li Dong-Ling;Zang Wei-Jin
胰岛素抵抗和自主神经失衡是代谢综合征引起的心脏重塑的重要病理过程。最近的研究确定线粒体嵴形状的破坏与心肌缺血有关。然而，代谢综合征引起的心脏重塑中嵴形状的变化仍不清楚。本研究确定了吡啶斯的明 (PYR) 对高脂饮食 (HFD) 诱导的心脏胰岛素抵抗的影响，并探讨了其对线粒体嵴形状的潜在影响。吡斯的明 (PYR) 可逆性抑制胆碱酯酶以改善自主神经失衡。饲喂 HFD 22 周会导致心脏线粒体嵴结构不规则甚至溶解，导致线粒体含量和 ATP 生成减少，氧生成增加，最终损害胰岛素信号传导和脂质代谢。有趣的是，PYR 通过增加乙酰胆碱的产生来增强迷走神经活性，并通过激活 LKB1/AMPK/ACC 信号通路发挥线粒体保护作用。具体来说，PYR上调OPA1和Mfn1/2的表达，促进mitofilin/CHCHD3/Sam50复合物的形成，并减少p-Drp1和Fis1的表达，导致嵴紧密且平行，增加心脏线粒体复合物亚基表达和ATP生成，并减少线粒体释放细胞色素C和氧化损伤。此外，PYR 改善了葡萄糖和胰岛素耐受性以及胰岛素刺激的 Akt 磷酸化，降低了脂质毒性，并最终改善了 HFD 诱导的心脏重塑和功能障碍。总之，在 HFD 诱导的小鼠代谢综合征中，PYR 通过刺激迷走神经活动来调节线粒体嵴形状和功能，从而预防心脏和胰岛素不敏感和重塑。这些结果为开发针对线粒体嵴的肥胖引起的心脏功能障碍的治疗策略提供了新的见解。
Insulin resistance and autonomic imbalance are important pathological processes in metabolic syndrome–induced cardiac remodeling. Recent studies determined that disruption of mitochondrial cristae shape is associated with myocardial ischemia; however, the change in cristae shape in metabolic syndrome–induced cardiac remodeling remains unclear. This study determined the effect of pyridostigmine (PYR), which reversibly inhibits cholinesterase to improve autonomic imbalance, on high-fat diet (HFD)–induced cardiac insulin resistance and explored the potential effect on the shape of mitochondrial cristae. Feeding of a HFD for 22 weeks led to an irregular and even lysed cristae structure in cardiac mitochondria, which contributed to decreased mitochondrial content and ATP production and increased oxygen species production, ultimately impairing insulin signaling and lipid metabolism. Interestingly, PYR enhanced vagal activity by increasing acetylcholine production and exerted mito-protective effects by activating the LKB1/AMPK/ACC signal pathway. Specifically, PYR upregulated OPA1 and Mfn1/2 expression, promoted the formation of the mitofilin/CHCHD3/Sam50 complex, and decreased p-Drp1 and Fis1 expression, resulting in tight and parallel cristae and increasing cardiac mitochondrial complex subunit expression and ATP generation as well as decreasing release of cytochrome C from mitochondria and oxidative damage. Furthermore, PYR improved glucose and insulin tolerance and insulin-stimulated Akt phosphorylation, decreased lipid toxicity, and ultimately ameliorated HFD-induced cardiac remodeling and dysfunction. In conclusion, PYR prevented cardiac and insulin insensitivity and remodeling by stimulating vagal activity to regulate mitochondrial cristae shape and function in HFD-induced metabolic syndrome in mice. These results provide novel insights for the development of a therapeutic strategy for obesity-induced cardiac dysfunction that targets mitochondrial cristae.
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DOI：
10.1096/fasebj.22.2_supplement.620
发表时间：
2008-04
期刊：
The FASEB Journal
影响因子：
--
作者：
K. Jóźwiak;R. Moaddel;I. Wainer;H. Arias
通讯作者：
K. Jóźwiak;R. Moaddel;I. Wainer;H. Arias
影响因子：
7.7
作者：
Vial, Guillaume;Chauvin, Marie-Agnes;Rieusset, Jennifer
通讯作者：
Rieusset, Jennifer
影响因子：
29
作者：
Civiletto G;Varanita T;Cerutti R;Gorletta T;Barbaro S;Marchet S;Lamperti C;Viscomi C;Scorrano L;Zeviani M
通讯作者：
Zeviani M
影响因子：
15.9
作者：
Furukawa, S.;Fujita, T.;Shimomura, I.
通讯作者：
Shimomura, I.
影响因子：
7.7
作者：
Reno, Candace M.;Puente, Erwin C.;Fisher, Simon J.
通讯作者：
Fisher, Simon J.