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PO3-3-13

Pyridostigmine improved macrophage polarization and cardiac fibrosis induced by isoproterenol in mice

[Speaker] Dong-Ling Li:1
[Co-author] Su-Yun Yong:1, Run-Qing Xue:1, Xiao-Jiang Yu:1, Wei-Jin Zang:1
1:Department of Pharmacology, School of Basic Medical Sciences, Xian Jiaotong University Health Science Center, China

Background
Cardiac fibrosis is the chronic inflammatory response to myocardial injury, which the monocyte/macrophage play the important role. This study found the effects of pyridostigmine (PYR), a reversible acetylcholinesterase inhibitor, on macrophage polarization and cardiac fibrosis induced by isoproterenol (ISO) in mice.

Methods
Mice were randomly divided into four groups (n=12), including (1) control; (2) 20mg/kg/d ISO s.c.; (3) ISO + 3mg/kg/d PYR i.g.; (4) ISO + 30mg/kg/d propranolol (PPN) i.g.. After 3-week, cardiac function were determined with echocardiography. Cardiac fibrosis were observed by Masson's staining. TNF-α, MCP-1, TGF-β and IL-10 were examined with western blot. Tonic sympathetic and vagal influences on the heart were assessed by heart rate (HR) changes induced by autonomic blockade produced by propranolol and atropine, respectively. Phenotypes of monocytes and macrophages were detected by flow cytometry.

Results
1. ISO decreased significantly ejection fraction (EF), shortening fraction (FS) and the thickness of ventricle, and enhanced left ventricular internal dimension and left ventricle mass. PYR or PPN both ameliorated cardiac function, but the effects of PYR on EF and FS were better than PPN.
2. ISO induced cardiac fibrosis accompanied with the significant increases in TNF-α, MCP-1 and TGF-β. PYR partly abolished ISO-induced cardiac fibrosis and reduced TNF-α, MCP-1 and TGF-β, while augmented IL-10. PPN was similar to PYR, but did not affect IL-10.
3. The sympathetic tone (HR changes after propranolol) dramatically increased and the vagal tone (HR changes after atropine) decreased in ISO, which is abolished by PYR. PPN only partly augmented the vagal tone that was lower than PYR, while significantly down-regulated the increased sympathetic tone.
4. ISO enhanced the polarization macrophages-the classic pathway (M1: F4/80+, CD86+, CD206-) and the alternative pathway (M2: F4/80+, CD86-, CD206+), and Ly6Chigh monocytes. PYR decreased both M1 and M2, and increased Ly6Clow monocytes, which PPN on macrophages was lower than PYR.

Conclusion
PYR inhibited monocytes activation and M1/M2 polarization via decreased the sympathetic tone and increased the vagal tone to improve cardiac fibrosis induced by ISO.

This work was supported by grant from National Natural Science Foundation of China (No. 81300114; No. 81770293; No. 81473203)
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