Nerve growth factor (NGF) is involved in nerve sprouting, hyper-innervation, angiogenesis, anti-apoptosis, and preservation of cardiac function after myocardial infarction (MI). Positively modulating NGF expression may represent a novel pharmacological strategy to improve post-infarction prognosis. In this study, lentivirus encoding NGF short interfering RNA (siRNA) was prepared, and MI was modeled in the rat using left anterior descending coronary artery ligation. Rats were randomly grouped to receive intramyocardial injection of lentiviral solution containing NGF-siRNA (n = 19, MI-SiNGF group), lentiviral solution containing empty vector (n = 18, MI-GFP group) or 0.9% NaCl solution (n = 18, MI-control group), or to receive thoracotomy and pericardiotomy (n = 17, sham-operated group). At 1, 2, 4, and 8 wk after transduction, rats in the MI-control group had higher levels of NGF mRNA and protein than those in the sham-operated group, rats in the MI-GFP group showed similar levels as the MI-control group, and rats in the MI-SiNGF group had lower levels compared to the MI-GFP group, indicating that MI model was successfully established and NGF siRNA effectively inhibited the expression of NGF. At 8 wk, echocardiographic and hemodynamic studies revealed a more severe cardiac dysfunction in the MI-siRNA group compared to the MI-GFP group. Moreover, rats in the MI-siRNA group had lower mRNA and protein expression levels of tyrosine hydroxylase (TH) and growth-associated protein 43-positive nerve fibers (GAP-43) at both the infarcted border and within the non-infarcted left ventricles (LV). NGF silencing also reduced the vascular endothelial growth factor (VEGF) expression and decreased the arteriolar and capillary densities at the infarcted border compared to the MI-GFP group. Histological analysis indicated a large infarcted size in the MI-SiNGF group. These findings suggested that endogenous NGF silencing attenuated sympathetic nerve sprouting and angiogenesis, enlarged the infarct size, aggravated cardiac dysfunction, and potentially contributed to an unfavorable prognosis after MI.

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Background: Abnormal sympathetic innervation underlies both long-term hyperglycemia and myocardial infarction (MI). The incidence of ventricular arrhythmias (VAs) after MI is higher in diabetic than in nondiabetic patients. However, the exact mechanism remains unclear. In this study, we aimed to explore sympathetic neural remodeling after MI in diabetic rabbits and its relationship with VAs. Methods: Rabbits were randomly assigned to 4 groups: control, diabetes mellitus (DM), MI and diabetic myocardial infarction (DI). After electrophysiological experiments in vivo, immunohistochemistry and real-time RT-PCR were used to measure sympathetic innervations. To test the function of sympathetic nerve fibers, norepinephrine levels were measured by high-performance liquid chromatography. Results: The corrected QT interval and QT dispersion were significantly more prolonged with DI than other conditions. The density of tyrosine hydroxylase-positive fibers and corresponding mRNA abundance was significantly higher with DI than with DM and under control conditions, but was lower than with the MI group. Moreover, the distribution and structure of regenerated nerve was heterogeneous in DI rabbits. Norepinephrine content was higher in the DI group, and accompanied by an increased quantity of tyrosine hydroxylase-positive fibers. Conclusion: MI results in sympathetic neural remodeling in diabetic rabbits, which may be responsible in part for the increased occurrence of VAs.