Atorvastatin attenuates sympathetic hyperinnervation together with the augmentation of M2 macrophages in rats postmyocardial infarction

Abstract

SummaryObjectives: 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.

Modulation of Ion Channels in the Superior Cervical Ganglion Neurons by Myocardial Ischemia and Fluvastatin Treatment

“…Fluvastatin pretreatment reversed these changes in SCG neurons caused by MI injury. Fluvastatin can reduce the electrical activity of SCG neurons, consistent with the results in clinical and experimental studies that statins decrease sympathetic activity and effectively ameliorate cardiac sympathetic nerve remodeling ( Kim et al, 2009 ; Lewandowski et al, 2014 ; Yang et al, 2016 ).…”

“…Fluvastatin ameliorates cardiac sympathetic neural dysfunction in diabetic rats ( Matsuki et al, 2010 ). In addition, clinical and experimental studies have suggested that statins decrease sympathetic activity and effectively ameliorate cardiac sympathetic nerve remodeling ( Kim et al, 2009 ; Lewandowski et al, 2014 ; Yang et al, 2016 ), but its mechanism of direct protection actions on sympathetic nerve has not been fully characterized. In our experiments, the characteristics of the SCG including the electrical properties and mRNA expression of ion channels, as well as AP characteristics were significantly altered at different time points after MI.…”

“…They can reduce the nervous injury caused by ischemia reperfusion and prevent postoperative atrial fibrillation through autonomic modulation ( Liu and Li, 2006 ). In addition, clinical and experimental studies have suggested that statins can be used to decrease sympathetic activity ( Kim et al, 2009 ; Lewandowski et al, 2014 ; Yang et al, 2016 ). Yet, the peripheral mechanisms involving direct actions on post-ganglionic sympathetic neurons contributing to this effect are not known.…”

Regulation of macrophage migration in ischemic mouse hearts via an AKT2/NBA1/SPK1 pathway

“…Atorvastatin treatment exceeded the benefits of lipid level reduction alone [ 20 ]. Numerous studies have demonstrated the beneficial role of atorvastatin in cardiac remodeling [ 21 ] and macrophage migration [ 7 ].…”

Effects of Angiotensin Receptor Neprilysin Inhibitors on Inducibility of Ventricular Arrhythmias in Rats with Ischemic Cardiomyopathy

“…It shows up as a series of pathophysiological changes including myocardial denervation, nerve sprouting, sympathetic over-regeneration, and high domination, 5) ultimately developing into electrophysiological heterogeneity. 6) After the subacute period, fibrous and scar tissue replaces ischemic necrotic myocardium. The fibrous tissue could develop into regions of conduction block and form nonuniform anisotropy and slow conduction which may finally result in reentry substrate for sustained VAs.…”