Hasan Wohaib, Jama Abdi, Donohue Timothy, Wernli Gwenaelle, Onyszchuk Gregory, Al-Hafez Baraa, Bilgen Mehmet, Smith Peter G
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas 66160, USA.
Brain Res. 2006 Dec 8;1124(1):142-54. doi: 10.1016/j.brainres.2006.09.054. Epub 2006 Nov 7.
Sympathetic hyperinnervation occurs in human ventricular tissue after myocardial infarction and may contribute to arrhythmias. Aberrant sympathetic sprouting is associated with elevated nerve growth factor (NGF) in many contexts, including ventricular hyperinnervation. However, it is unclear whether cardiomyocytes or other cell types are responsible for increased NGF synthesis. In this study, left coronary arteries were ligated and ventricular tissue examined in rats 1-28 days post-infarction. Infarct and peri-infarct tissue was essentially devoid of sensory and parasympathetic nerves at all time points. However, areas of increased sympathetic nerve density were observed in the peri-infarct zone between post-ligation days 4-14. Hyperinnervation occurred in regions containing accumulations of macrophages and myofibroblasts. To assess whether these inflammatory cells synthesize NGF, sections were processed for NGF in situ hybridization and immunohistochemistry. Both macrophage1 antigen-positive macrophages and alpha-smooth muscle actin-immunoreactive myofibroblasts expressed NGF in areas where they were closely proximate to sympathetic nerves. To investigate whether NGF produced by peri-infarct cells induces sympathetic outgrowth, we co-cultured adult sympathetic ganglia with peri-infarct explants. Neurite outgrowth from sympathetic ganglia was significantly greater at post-ligation days 7-14 as compared to control tissue. Addition of an NGF function-blocking antibody prevented the increased neurite outgrowth induced by peri-infarct tissue. These findings provide evidence that inflammatory cell NGF synthesis plays a causal role in sympathetic hyperinnervation following myocardial infarction.
心肌梗死后人类心室组织会出现交感神经支配过度，这可能导致心律失常。在包括心室神经支配过度在内的许多情况下，异常的交感神经芽生与神经生长因子（NGF）升高有关。然而，尚不清楚是心肌细胞还是其他细胞类型导致NGF合成增加。在本研究中，结扎大鼠左冠状动脉，并在梗死后1 - 28天检查心室组织。在所有时间点，梗死和梗死周边组织基本没有感觉神经和副交感神经。然而，在结扎后第4 - 14天之间，梗死周边区域观察到交感神经密度增加。神经支配过度发生在含有巨噬细胞和成肌纤维细胞聚集的区域。为了评估这些炎性细胞是否合成NGF，对切片进行NGF原位杂交和免疫组织化学处理。巨噬细胞1抗原阳性的巨噬细胞和α - 平滑肌肌动蛋白免疫反应性成肌纤维细胞在靠近交感神经的区域均表达NGF。为了研究梗死周边细胞产生的NGF是否诱导交感神经生长，我们将成年交感神经节与梗死周边外植体共培养。与对照组织相比，结扎后第7 - 14天交感神经节的神经突生长明显增加。添加NGF功能阻断抗体可阻止梗死周边组织诱导的神经突生长增加。这些发现提供了证据，表明炎性细胞NGF合成在心肌梗死后交感神经支配过度中起因果作用。
