Norepinephrine and Nerve Growth Factor in Heart Failure

描述（由申请方提供）：心脏去甲肾上腺素能神经末梢 衰竭的心脏功能异常突触前和突触后 已经观察到异常。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 下调和心脏功能恶化。由于这些变化是 与神经生长因子（NGF）的减少有关，可以通过以下方法预防： 抗氧化维生素，这个应用程序旨在阐明相对 氧化应激和神经生长因子对肾上腺素能神经末梢功能的作用， 心力衰竭的心脏功能我们将测量蛋白质和mRNA 心脏神经生长因子表达，神经生长因子受体TrKA，组织氧化应激 （氧化型谷胱甘肽、羟自由基、线粒体DNA氧化 产品）和心肌细胞凋亡。这些发现 将与突触前心肌NE摄取部位密度（NE 组织荧光，酪氨酸羟化酶谱，以及突触后 心肌B-肾上腺素能受体密度和B-肾上腺素能敏感性以及心脏 功能超氧化物歧化酶和司来吉兰，已被证明可以防止 心脏交感神经异常在心力衰竭，将用于 确定它们的作用是否通过减少心脏NE介导 释放和氧化应激，和/或保存心脏NGF。研究还 将进行以确定卡维地洛在心脏中的有益作用 失败是通过其对a-或f3-受体的阻断作用介导的，或 与其抗氧化作用有关。研究表明， 心脏神经生长因子通过α-受体作用，而其凋亡作用是介导的 最后，将一个NGF小基因直接注射到 以确定它是否会对交感神经产生有益的影响 末梢和心脏功能。我们的研究不仅能阐明 机制负责去甲肾上腺素能神经末梢功能障碍，但也 为心力衰竭的治疗提供了一种潜在有用的新模式。

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.