Abstract
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.
Highlights
Myocardial infarction (MI) is a major cause of death and disability worldwide [1]
These data suggested that transduction was successfully performed, and nerve growth factor (NGF) short interfering RNA (siRNA) effectively inhibited the expression of NGF in infarcted hearts of rats in the MI-SiNGF group
Elevation of NGF expression may lead to sympathetic nerve sprouting which potentially contributes to the later genesis of arrhythmias but may favor the healing process [6]
Summary
Myocardial infarction (MI) is a major cause of death and disability worldwide [1]. Advances in medicine have markedly improved the long-term survival and quality of life in MI patients [2]. NGF is rapidly and persistently up-regulated to trigger sympathetic nerve sprouting in infarcted hearts [9,10] Both endogenous and ectogenic upregulation of NGF after MI can promote sympathetic nerve sprouting and hyper-innervation (neural remodeling) which contribute to arrhythmogenesis and sudden cardiac death [9,10,11,12]. Several publications described that drug interventions improve sympathetic nerve sprouting and inhibite hyper-innervation partly by down-regulating myocardial NGF expression in infarcted hearts [13,14,15,16]. 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
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