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

目前的SCOR和拟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，无论是表现为肥厚还是扩张，无论是遗传的还是后天的。本SCOR项目5的总体目标是确定在收缩性心力衰竭中，肿瘤坏死因子-α(TNF-α)和肾素-血管紧张素系统(RAS)之间是否存在临床上显著的相互作用。这将通过处理四个合乎逻辑和相辅相成的具体目标来实现。在具体目标1中，我们将确定病理生理上相关的血管紧张素II(Ang II)浓度是否足以刺激成人心脏中的TNF-α生物合成，以及确定在心脏中病理生理学浓度升高的Ang II的效应(心肌细胞坏死、细胞凋亡和心肌纤维化)是否至少部分地由TNF-α介导。在特定的目标2中，我们将确定心脏限制性过表达的肿瘤坏死因子-α是否会导致心肌肾素血管紧张素系统的激活增加，以及心脏限制性过度表达肿瘤坏死因子-α对心肌结构的有害影响(左心室扩张、纤维化和心肌细胞凋亡)是否至少部分地通过激活心肌RAS而介导。因此，在特定的目标1和2中，我们将确定神经激素和细胞因子相互作用在心脏中的存在和功能意义。在特定的目标2中，我们将确定血管紧张素II和肿瘤坏死因子-α是否会聚在一组共同的丝裂原激活蛋白(MAP)激酶通路上，以及血管紧张素II和肿瘤坏死因子-α同时刺激是否会通过涉及“应激激活”的MAP激酶(JNK和/或p38)过度激活的途径来刺激心肌细胞凋亡。最后，在特定的目标4中，我们建议将上述问题扩展到“床边”，通过确定扩张型心肌病患者的肾素血管紧张素系统和肿瘤坏死因子-α之间是否存在相互作用，通过随机将患者分配到特异性拮抗肾素血管紧张素系统、肿瘤坏死因子-α或两者兼有的临床治疗组，然后检查这些治疗干预对心肌RAS、心肌肿瘤坏死因子-α-心肌MAP激酶和心肌细胞凋亡的影响。

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.