Metoprolol-Mediated Amelioration of Sympathetic Nerve Sprouting after Myocardial Infarction

Abstract

Objectives: Systemic or local inflammation causes cardiac nerve sprouting and consequent arrhythmia. Metoprolol can prevent sympathetic nerve remodeling after myocardial infarction (MI), but the underlying mechanism is unclear. In this study, we evaluated the role of metoprolol in ameliorating sympathetic sprouting. Methods: Rabbits underwent ligation of the coronary artery for MI. MI rabbits received metoprolol or saline for 7 days. Immunohistochemistry was used to measure cardiac nerve sprouting and sympathetic innervations. Nuclear factor-κB (NF-κB) DNA binding activity was analyzed by electrophoretic mobility shift assay. The protein levels of NF-κB p65, inhibitor κBa (IκBa) and nerve growth factor (NGF) were detected by Western blot analysis. The mRNA levels of NGF, interleukin-1ß (IL-1ß) and tumor necrosis factor-a (TNF-a) were examined by quantitative real-time PCR. Results: MI rabbits showed nerve sprouting and sympathetic hyperinnervation. In MI rabbits, as compared with saline treatment, metoprolol reduced NF-κB DNA binding activity and NF-κB p65 level, and increased IκBa level. Moreover, metoprolol downregulated IL-1ß, TNF-a and NGF levels, and reduced the density of sympathetic nerve fibers. Conclusions: Metoprolol ameliorates sympathetic nerve sprouting in rabbits after MI and is associated in part with inhibiting NF-κB activity.

Targeted NGF siRNA Delivery Attenuates Sympathetic Nerve Sprouting and Deteriorates Cardiac Dysfunction in Rats with Myocardial Infarction

“…Previous studies have showed that dexamethasone [14], nicorandil [15], and metoprolol [13] can improve sympathetic nerve remodeling partly through down-regulating NGF. Infarct size is not significantly affected in resveratrol-treated infarcted rats which have a decreased NGF level [16].…”

“…Both endogenous and ectogenic up-regulation of NGF after MI can promote sympathetic nerve sprouting and hyper-innervation (neural remodeling) which contribute to arrhythmogenesis and sudden cardiac death [9]–[12]. Furthermore, several publications described that drug interventions improve sympathetic nerve sprouting and inhibite hyper-innervation partly by down-regulating myocardial NGF expression in infarcted hearts [13]–[16]. These findings indicate that modulation of NGF expression could regulate sympathetic innervation patterns, providing potential access points for novel therapeutic strategies to prevent lethal arrhythmias and sudden cardiac death.…”

Semaphorin 3A attenuates cardiac autonomic disorders and reduces inducible ventricular arrhythmias in rats with experimental myocardial infarction

“…Consistently, in the MI-SiRNA group, higher levels of NE were detected accompanied with a higher arrhythmic score and an increased incidence of inducible VAs. Previous studies revealed that sympathetic hyperinnervation and activation were correlated with a high incidence of lethal VAs and sudden cardiac death in post-infarcted hearts [ 5 , 7 , 8 , 30 ]. In addition, pro-arrhythmia effects were reported in sema 3A-related neural remodeling animals [ 16 , 19 ].…”

Metoprolol protects against myocardial infarction by inhibiting miR-1 expression in rats

“…Studies have shown that metoprolol could inhibit ventricular remodelling and sympathetic nerve sprouting after MI by decreasing level of proinflammatory cytokines TNF-a and IL-1b and increasing level of anti-inflammatory cytokines IL-10. [25,26] Similarly, metoprolol could also have a positive therapeutic effect on MI rats by inhibiting proto-oncogene c-Fos. [27] Recently, miRNAs are emerged as drug targets for cardiovascular diseases.…”