Clinical significance of TNF alpha/RAS cross-talk in the failing heart

TNF α/RAS 串扰在衰竭心脏中的临床意义

• 批准号: 6564974
• 负责人: Douglas L Mann
• 金额: $ 18.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564974
• 关键词: JUN kinase; angiotensin II; apoptosis; calcium flux; cardiac myocytes; cats; clinical research; fibrosis; genetically modified animals; heart failure; human subject; idiopathic dilated cardiomyopathy; laboratory mouse; mitogen activated protein kinase; norepinephrine; renin angiotensin system; tumor necrosis factor alpha

The overall goal of the current SCOR and the PROPOSED RENEWAL is to elucidate the molecular basis for the long-term adaptive responses of the heart to injury, both inherited and acquired, whether manifested by hypertrophy or dilation. The overall goal of Project 5 of this SCOR is to determine whether there is a clinically significant interaction between tumor necrosis factor-alpha (TNF-alpha) and the renin-angiotensin system (RAS) in systolic heart failure. This will be accomplished by addressing a series of four logical and mutually complementary specific aims. In Specific Aim 1 we will determine whether pathophysiologically relevant concentrations of angiotensin II (Ang II) are sufficient to provoke TNF- alpha biosynthesis in the adult heart, as well as to determine whether the effects (myocyte necrosis, apoptosis and myocardial fibrosis) of pathophysiologically elevated concentrates of Ang II in the heart are mediated, at least in part, by TNF-alpha. In Specific Aim 2 we will determine whether cardiac restricted over-expression of TNF-alpha will lead to increased activation of the myocardial renin angiotensin system, and whether the deleterious effects of cardiac restricted over-expression of TNF-alpha on myocardial structure (LV dilation, fibrosis and myocyte apoptosis) are mediated, at least in part, through activation of myocardial RAS. Thus, in Specific Aims 1 and 2 we will establish the presence and functional significance of neurohormonal and cytokine interactions in the heart. In Specific Aim 2 we will determine whether angiotensin II and TNF-alpha converge on a common set of mitogen activated protein (MAP) kinase pathways, as well as whether concurrent stimulation with angiotensin II and TNF-alpha will provoke apoptosis in cardiac myocytes through a pathway that involves excessive activation of "stress activated" MAP kinases (JNK and/or p38). Finally, in Specific Aim 4 we propose to extend the above questions to the "bedside", by determining whether there is an interaction between the renin angiotensin system and TNF-alpha in patient with dilated cardiomyopathy, by randomizing patients to clinical treatments arms that specifically antagonize the renin angiotensin system, TNF-alpha or both, and then examining the impact on these therapeutic interventions on the activation of myocardial RAS, myocardial TNF- alpha-myocardial MAP kinases and cardiac myocyte apoptosis.

当前SCOR和提议的更新的总体目标是阐明心脏对损伤的长期适应性反应的分子基础，包括遗传性和获得性，无论表现为肥大还是扩张。本SCOR项目5的总体目标是确定肿瘤坏死因子-α（TNF-α）和肾素-血管紧张素系统（RAS）在收缩性心力衰竭中是否存在具有临床意义的相互作用。这将通过处理一系列四个逻辑和相辅相成的具体目标来实现。在具体目标1中，我们将确定血管紧张素II（Ang II）的病理生理相关浓度是否足以激发成人心脏中的TNF-α生物合成，以及确定病理生理升高的浓度的影响（肌细胞坏死、细胞凋亡和心肌纤维化）是否心脏中的Ang II至少部分由TNF-α介导。在特定目标2中，我们将确定心脏限制性TNF-α过表达是否会导致心肌肾素血管紧张素系统激活增加，以及心脏限制性TNF-α过表达对心肌结构（LV扩张、纤维化和心肌细胞凋亡）的有害作用是否至少部分通过心肌RAS激活介导。因此，在具体目标1和2中，我们将确定心脏中神经激素和细胞因子相互作用的存在和功能意义。在特定目标2中，我们将确定血管紧张素II和TNF-α是否汇聚在一组共同的促分裂原活化蛋白（MAP）激酶通路上，以及血管紧张素II和TNF-α的同时刺激是否会通过过度激活“应激活化”MAP激酶（JNK和/或p38）的通路引起心肌细胞凋亡。最后，在具体目标4中，我们建议将上述问题扩展到“床旁”，通过确定扩张型心肌病患者中的肾素血管紧张素系统和TNF-α之间是否存在相互作用，通过将患者随机分配至特异性拮抗肾素血管紧张素系统、TNF-α或两者的临床治疗组，然后检查这些治疗干预对心肌RAS、心肌TNF-α-心肌MAP激酶和心肌细胞凋亡的激活的影响。