Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, PO Box 77#, No.76 Yanta West Road, Xi'an City, 710061, Shaanxi Province, PR China.
Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, PO Box 77#, No.76 Yanta West Road, Xi'an City, 710061, Shaanxi Province, PR China.
Free Radic Biol Med. 2019 Apr;134:119-132. doi: 10.1016/j.freeradbiomed.2019.01.011. Epub 2019 Jan 10.
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.
胰岛素抵抗和自主神经失衡是代谢综合征引起的心脏重构的重要病理过程。最近的研究表明，线粒体嵴形态的破坏与心肌缺血有关；然而，代谢综合征引起的心脏重构中线粒体嵴形态的变化尚不清楚。本研究旨在确定可逆抑制胆碱酯酶以改善自主神经失衡的吡啶斯的明（PYR）对高脂肪饮食（HFD）诱导的心脏胰岛素抵抗的影响，并探讨其对线粒体嵴形态的潜在影响。喂养 HFD22 周导致心脏线粒体嵴结构不规则甚至裂解，这导致线粒体含量和 ATP 产生减少，氧自由基产生增加，最终损害胰岛素信号和脂质代谢。有趣的是，PYR 通过增加乙酰胆碱的产生增强了迷走神经活动，并通过激活 LKB1/AMPK/ACC 信号通路发挥了线粒体保护作用。具体而言，PYR 上调了 OPA1 和 Mfn1/2 的表达，促进了 mito 形成 - 联蛋白/CHCHD3/Sam50 复合物，并降低了 p-Drp1 和 Fis1 的表达，导致嵴紧密且平行，增加了心脏线粒体复合物亚基的表达和 ATP 的产生，并减少了细胞色素 C 从线粒体中的释放和氧化损伤。此外，PYR 改善了葡萄糖和胰岛素耐量以及胰岛素刺激的 Akt 磷酸化，降低了脂质毒性，最终改善了 HFD 诱导的心脏重构和功能障碍。总之，PYR 通过刺激迷走神经活动来调节 HFD 诱导的代谢综合征中小鼠线粒体嵴的形态和功能，防止了心脏和胰岛素的不敏感和重构。这些结果为针对肥胖引起的心脏功能障碍的线粒体嵴靶向治疗策略的发展提供了新的思路。
