Norepinephrine and Nerve Growth Factor in Heart Failure

描述(申请人提供)：心脏去甲肾上腺素能神经末梢 衰竭心脏的功能是不正常的。突触前和突触后 观察到了异常情况。它们包括去甲肾上腺素(NE)耗竭， 神经元NE摄取活性降低，间质NE、F3肾上腺素受体增加 心功能下调和恶化。由于更改是 与神经生长因子(NGF)减少有关，并可通过以下方法预防 抗氧化维生素，这一应用旨在阐明与之相关的 氧化应激和神经生长因子对肾上腺素能神经末梢功能的影响 心力衰竭时的心功能。我们将测量蛋白质和信使核糖核酸 心肌NGF及其受体TrkA、组织氧化应激的表达 (氧化谷胱甘肽、羟基自由基、线粒体DNA氧化 产品)和起搏诱导的心肌病中的心肌细胞凋亡。调查结果 将与突触前心肌去甲肾上腺素摄取部位密度，NE 组织荧光、酪氨酸羟化酶图谱以及突触后 心肌B受体密度和B肾上腺素能敏感性与心脏 功能。超氧化物歧化酶和司来吉兰，已被证明可以防止 心力衰竭时的心脏交感神经异常，将用于 确定它们的作用是否通过降低心脏去甲肾上腺素来实现 释放和氧化应激，和/或保存心脏NGF。研究亦包括 将进行检查以确定卡维地洛对心脏的有益作用 失败是通过它对a-或f3-受体的阻断作用来调节的，或者 与其抗氧化作用有因果关系。研究表明，去甲肾上腺素减少 心脏NGF通过a受体的作用，而其凋亡效应是通过介导的 最后，通过B受体，NGF微型基因将直接注射到 心脏以确定它是否会对交感神经产生有益作用 结局和心脏功能。我们的研究不仅将阐明 去甲肾上腺素能神经末梢功能障碍的机制，但也 为心力衰竭的治疗提供了一种潜在有用的新方法。

DESCRIPTION (provided by applicant): Cardiac noradrenergic nerve terminal function is abnormal in the failing heart. Both presynaptic and postsynaptic abnormalities have been observed. They include norepinepbrine (NE) depletion, reduced neuronal NE uptake activity, increased interstitial NE, f3-adrenoceptor down-regulation and deterioration of cardiac function. Since the changes are associated with a decrease of nerve growth factor (NGF), and can e prevented by antioxidant vitamins, this application is designed to elucidate the relative roles of oxidative stress and NGF on the adrenergic nerve terminal function and cardiac function in heart failure. We will measure the protein and mRNA expressions of cardiac NGF, NGF receptor TrKA, tissue oxidative stress (oxidized glutathione, hydroxyl free radicals, mitochondria DNA oxidation products) and myocyte apoptosis in pacing-induced cardiomyopathy. The findings will be correlated to the presynaptic myocardial NE uptake site density, NE histofluorescence, tyrosine hydroxylase profiles, as well as the postsynaptic myocardial B-adrenoceptor density and B-adrenergic sensitivity and cardiac function. Superoxide dismutase and selegiline, which have been shown to prevent cardiac sympathetic nerve abnormalities in heart failure, will be used to determine whether their effects are mediated via reductions of cardiac NE release and oxidative stress, and/or preservation of cardiac NGF. Studies also will be performed to determine if the beneficial effects of carvedilol in heart failure are mediated via its blocking actions on the a- or f3-receptors, or related causally to its antioxidant effect. Studies have shown that NE reduces cardiac NGF by an a-receptor action, whereas its apoptotic effects are mediated via the B-receptors Finally, a NGF minigene will be injected directly into the heart to determine if it will produce salutary effects on sympathetic nerve endings and cardiac function. Our research will not only elucidate the mechanisms responsible for noradrenergic nerve ending dysfunction, but also provide a potentially useful new modality for the treatment of heart failure.