Pyridostigmine exerts cardiovascular protection effects via ameliorating damaged mitochondrial cristae in high fat diet-induced obese mice

[Speaker] Run-Qing Xue:1
[Co-author] Yan-Ling Cui:1, Xiao-Jiang Yu:1, Dong-Ling Li:1, Long-Zhu Liu:1, Wei-Jin Zang:1
1:Department of Pharmacology, School of Basic Medical Sciences, Xian Jiaotong University Health Science Center, Xi an, Shaanxi, China

Background: Autonomic and mitochondrial dysfunction results in cardiovascular damage in obesity. Mitochondrial cristae are bioenergetic compartments and shape changes with pathological conditions. However there are no substantial studies to assess what is the function of mitochondrial cristae in obesity-induced cardiovascular disease. This study investigated the role of mitochondrial cristae in high fat diet (HFD)-induced cardiac remodeling and vascular dysfunction and explored the protective effects of pyridostigmine (PYR).

Methods: 6-week-old C57BL/6 male mice were fed a HFD or normal control diet (control) and administrated intragastrically with saline or PYR (3 mg/kg per day) for 22 weeks. After 22-week, mice cardiac and thoracic aorta function were recorded respectively by echocardiography and myograph system. Cardiac acetylcholine and acetylcholinesterase content were measured by Elisa kit. Dihydroethidium staining was used to determine ROS content in mice heart tissue. Cardiac mitochondrial arrangement and cristae were observed by transmission electron microscopy. Western blot was used to detect mitochondrial-shaping and respiratory chain proteins.

Results: (1) HFD induced cardiac remodeling and vascular damage, accompanied with increased mitochondrial number and decreased mitochondrial volume and cristae junctions and density. HFD also decreased the protein express of mitochondrial-shaping proteins, complex I, II, III, IV, V and cytochrome C and led to ROS production in mice heart. (2) PYR up-regulated cardiac acetylcholine and down-regulated acetylcholinesterase content, thus partly recued the imbalance of autonomic nervous in heart of HFD mice. Treatment with PYR also markedly reduced body weight and ameliorated HFD-induced cardiac remodeling and vascular injury compared with control mice. (3) Importantly, PYR promoted the expression of OPA1 and the formation of mitofilin/CHCHD3/SAMM50 complex, which strengthened mitochondrial cristae junctions and improved mitochondrial density, therefore protected mitochondrial respiratory chain and declined the release of cytochrome C and the production of ROS in heart of HFD mice.

Conclusions: HFD induced cardiac remodeling and vascular dysfunction, which was associated with damaged mitochondrial cristae. PYR partly improved the balance of cardiac autonomic nervous and protected mitochondrial cristae structure through regulating OPA1 and mitofilin/CHCHD3/SAMM50 complex, thus deduced mitochondrial damage and restored HFD-induced cardiovascular dysfunction.

This work was supported by grant from National Natural Science Foundation of China (No.81770293; No.81473203).
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