ANGIOTENSIN II-SMAD SIGNALING IN CARDIAC FIBROSIS

心脏纤维化中的血管紧张素 II-SMAD 信号传导

• 批准号: 7176083
• 负责人: MARK L ENTMAN
• 金额: $ 33.78万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-09 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7176083
• 关键词: Acute; Affect; Angiotensin II; Angiotensins; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Chronic Disease; Clinical; Clinical Trials; Coculture Techniques; Collagen; Condition; Development; Diabetes Mellitus; Disease; Dominant-Negative Mutation; Dose; Elements; Embryo; Fibroblasts; Fibrosis; Heart; Heart Diseases; Hour; Hypertension; In Vitro; Infusion procedures; Kidney; Knock-out; Knockout Mice; Lead; Long-Term Effects; MAPK14 gene; Mediating; Mediator of activation protein; Messenger RNA; Mus; Muscle Cells; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Play; Production; Protein Overexpression; Proteins; Research Personnel; Role; Signal Pathway; Signal Transduction; Testing; Thinking; Tissues; Wild Type Mouse; autocrine; base; human MAPK14 protein; hypertensive heart disease; in vivo; inhibitor/antagonist; insight; mRNA Expression; mitogen-activated protein kinase p38; novel therapeutics; prevent; programs; receptor; response; salt sensitive; subcutaneous

DESCRIPTION (provided by applicant): Ang II plays a pivotal role in chronic cardiac disease, however, its signaling pathways leading to cardiac fibrosis remain largely unclear. It is known that Ang II acts by stimulating TGF-b to mediate cardiac fibrosis, however, our preliminary studies found that Ang II is able to directly activate the TGF-b signaling pathway by two mechanisms: 1) an acute pathway (5-30 minutes) via activation of the ERK/p38 MAP kinases. This is TGF-b-independent since Ang II is able to activate Smad2 &3 in cells lacking TGF-b receptors; this response is blocked by ERK or p38 inhibitors; 2) a late mechanism (24 hours) that acts through autocrine TGF-b and leads to fibrosis. Furthermore, we also found that mice null for SmadS are protected against cardiac fibrosis, while mice that are conditionally deleted for Smad2 enhance fibrosis in response to Ang II. Thus, we hypothesize that Smad signaling is a key to the development of cardiac fibrosis in response to Ang II. We plan to test this hypothesis by pursuing three specific aims. In Specific Aim 1, we propose to identify new signaling pathways whereby Ang II mediates cardiac fibrosis. We will demonstrate that Ang II signals through the AT1-R and activates an acute Smad signaling via the ERK/p38 MAPK-dependent mechanism (5-30 mins). We also propose to identify that a long-term effect of Ang II by activating a late Smad signaling via the classic TGF-b-dependent mechanism (24hrs). In Specific Aim 2, we will dissect the specific role of Smad2 or SmadS in Ang ll-mediated fibrosis in mouse embryonic fibroblasts lacking Smad2 or SmadS and in cardiac fibroblasts that do not express SmadS or have conditional knockout for Smad2. In Specific Aim 3, we will further investigate the functional role of Smad2 or SmadS in cardiac fibrosis in mice null for SmadS KO mice or have conditional KO for Smad2 by subcutaneous infusion of large doses of Ang II. We expect that the outcomes obtained will support the central hypothesis, providing new insights into the pathogenesis of Ang ll-mediated cardiac fibrosis and information for the development of new therapeutic strategies.

描述（申请人提供）：血管紧张素II在慢性心脏病中起着关键作用，然而，其导致心脏纤维化的信号通路仍不清楚。已知Ang II通过刺激TGF-β介导心脏纤维化，然而，我们的初步研究发现Ang II能够通过两种机制直接激活TGF-β信号通路：1）通过激活ERK/p38 MAP激酶的急性通路（5-30分钟）。这是不依赖于TGF-β的，因为Ang II能够在缺乏TGF-β受体的细胞中激活Smad 2和3;这种反应被ERK或p38抑制剂阻断; 2）通过自分泌TGF-β起作用并导致纤维化的晚期机制（24小时）。此外，我们还发现，SmadS缺失的小鼠可保护其免受心脏纤维化，而Smad 2有条件缺失的小鼠可增强对Ang II的反应性纤维化。因此，我们推测Smad信号是血管紧张素II引起心脏纤维化的关键。我们计划通过追求三个具体目标来验证这一假设。在具体目标1，我们建议确定新的信号通路，血管紧张素II介导的心脏纤维化。我们将证明Ang II通过AT 1-R信号传导并通过ERK/p38 MAPK依赖性机制激活急性Smad信号传导（5-30分钟）。我们还提出通过经典的TGF-β依赖性机制（24小时）激活晚期Smad信号来鉴定Ang II的长期作用。在具体目标2中，我们将剖析Smad 2或SmadS在缺乏Smad 2或SmadS的小鼠胚胎成纤维细胞和不表达SmadS或具有Smad 2的条件性敲除的心脏成纤维细胞中Ang II介导的纤维化中的具体作用。在特定目标3中，我们将进一步研究Smad 2或SmadS在SmadS KO小鼠或通过皮下输注大剂量Ang II对Smad 2进行条件性KO的小鼠中心脏纤维化中的功能作用。我们期望所获得的结果将支持中心假设，为Ang II介导的心脏纤维化的发病机制提供新的见解，并为开发新的治疗策略提供信息。