title: Atorvastatin attenuates sympathetic hyperinnervation together with the augmentation of M2 macrophages in rats postmyocardial infarction.
abstract: OBJECTIVE
  Inflammation after myocardial infarction (MI) causes cardiac nerve sprouting and consequent ventricular arrhythmias (VAs). Macrophages, as major immune cells, are involved in the entire inflammation response process and serve as a link between inflammation and sympathetic hyperinnervation by regulating nerve growth factor (NGF) expression. Accumulating evidence shows that statins possess antiarrhythmogenic properties, and the aim of this study was to explore the mechanism by which atorvastatin ameliorates cardiac sympathetic nerve sprouting via regulating macrophage polarization.
  
  
  METHODS
  Rat models of MI were created by ligating the left coronary artery. MI-operated rats received either atorvastatin or phosphate-buffered saline for 7 days. Immunohistochemical analyses and immunofluorescence staining were used to analyze macrophage infiltration after MI and to detect the distribution and density of growth-associated protein-43 (GAP-43) and tyrosine hydroxylase (TH) in nerve fibers in peri-infarct zones after MI. The polarity of the macrophages that were obtained from the rat peritoneal cavity was examined via flow cytometry. The protein levels of NGF were detected via Western blot analysis, and the concentrations of NGF in the supernatants were determined via enzyme-linked immunosorbent assay. The mRNA levels of NGF, inducible nitric oxide synthase (iNOS), Arginase-1 (Arg1), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) were examined by quantitative real-time polymerase chain reaction. The association between VAs and MI was evaluated using programmed electrophysiological stimulation.
  
  
  RESULTS
  Macrophages were successfully induced to the M1 (classically activated) and M2 (alternatively activated) phenotypes by stimulation with lipopolysaccharide and interferon-γ (LPS + IFN-γ) and interleukin-4 (IL-4), respectively. Atorvastatin markedly downregulated IL-1β, TNF-α, iNOS, and NGF and upregulated Arg1, shifting the macrophage phenotype from M1 to M2. Moreover, atorvastatin significantly reduced TH levels and the density of GAP-43-positive nerve fibers and decreased inducible VAs.
  
  
  CONCLUSIONS
  Atorvastatin effectively ameliorated cardiac sympathetic nerve remodeling and prevented VAs after MI by significantly downregulating the expression of NGF, IL-1β, and TNF-α via together with the augmentation of M2 macrophage.
authors.affiliation: Department of Cardiology, School of Medicine, Shandong University, Ji'nan, Shandong, China.
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong, China.
authors.forename: Hesheng
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Xue
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong, China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, School of Medicine, Shandong University, Ji'nan, Shandong, China.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Xuan
authors.affiliation: Department of Cardiology, School of Medicine, Shandong University, Ji'nan, Shandong, China.
authors.forename: Xinran
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, School of Medicine, Shandong University, Ji'nan, Shandong, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Cardiology, School of Medicine, Shandong University, Ji'nan, Shandong, China.
authors.forename: Yugen
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong, China.
authors.forename: Suhua
authors.initials: S
authors.lastname: Yan
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D000069059:Atorvastatin / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019922:GAP-43 Protein / Q000378:metabolism; D006321:Heart / Q000294:innervation*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D017180:Tachycardia, Ventricular / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D000889:Anti-Arrhythmia Agents; D000893:Anti-Inflammatory Agents; D019922:GAP-43 Protein; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D020932:Nerve Growth Factor; D000069059:Atorvastatin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D014446:Tyrosine 3-Monooxygenase; D001119:Arginase; C542908:arginase I, rat
keywords: Atorvastatin; Inflammation; Macrophage polarization; Myocardial infarction; Sympathetic nerve