Role of IGF-1 Signaling and MAP Kinases in Cardiac Hypertrophy

IGF-1 信号传导和 MAP 激酶在心脏肥大中的作用

• 批准号: 7163120
• 负责人: GEORGES E. HADDAD
• 金额: $ 21.69万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7163120
• 关键词: angiotensin II; apoptosis; biological signal transduction; calcium channel; enzyme activity; guanine nucleotide binding protein; heart enlargement; heart failure; insulinlike growth factor; mitogen activated protein kinase; myocardium; phosphatidylinositol 3 kinase; potassium channel; tissue /cell culture; ventricular hypertrophy

Cardiac hypertrphy is the most important contributor to cardiovascular morbidity and mortality in western societies. Caridac hypertrophy develops in order to maintain cardiac function against an increasing workload. Early in the process, this hypertrophic response may be beneficial but sustained hypertrophic activation ultimately leads to myocardial dysfunction. Interestingly, the intracellular pathways controlling the development of hypertrophy and which mediate the progression from hypertrophy to heart failure are unclear. Timely activation of humoral factors, such angiotensin II (ANG II) and insulin-like-growth factor-1 (IGF-1), delineate the activation processes of specific protein kinases whose integrated responses leads to the early beneficial cardiac hypertrophy and later to heart failure. IGF-1 administration can induce hypertrophy as well as block cardiac apoptosis; however ANG II can activate both processes. In the heart, activation of phophatidylinositol (PI) 3-kinase is critical to the ability of IGF-1 to block apoptosis. In contrast, the Ras/MAP (mitogen-activated protein) kinase pathway, which can be activated by both IGF-1 and ANG II, has been associated with cardiac hypertrophy. We have found that compensated eccentric cardiac hypertrophy is associated with enhanced activation of these kinases; whereby alterations in potassium and calcium ion channels induced by ANG II and IGF-1 are mainly mediated through MAP kinase and PI 3- kinase activation. The goals of this porposal is to understand the biological roles of specific downstream signaling pathways in controlling cardiocyte apoptosis and hypertrophy, and to delineate the contribution of apoptosis to the development of heart failure. This porposal is based on 3 hypotheses: 1) signaling pathways responsible for the ability of IGF-1 to induce hypertrophy and block apoptosis are distinct; 2) activation of PI 3-kinase accounts for the benefial effects of IGF-1 on cardiocyte survival; and 3) apoptosis contributes to the development of cardiac dysfunctin in heart failure. To test these hypotheses, we will use adenoviral vectors to express wild-type and mutant-forms of specific signaling molecules in cardiocytes. The long term goal is understanding the role of specific signaling pathways in cardiocyte apoptosis and developing approaches to local modulation of these pathways through somatic gene transfer; which may provide novel therapeutic appraoches for the management of many clinically important disorders.

心脏肥大是西方国家心血管疾病发病率和死亡率的最重要因素 社团。心脏肥大的发展是为了维持心脏功能以应对日益增加的心脏功能 工作量。在此过程的早期，这种肥大反应可能是有益的，但会持续肥大 激活最终导致心肌功能障碍。有趣的是，细胞内途径控制 肥厚的发展以及介导从肥厚到心力衰竭的进展是 不清楚。及时激活体液因子，如血管紧张素 II (ANG II) 和胰岛素样生长因子-1 (IGF-1)，描述特定蛋白激酶的激活过程，其综合反应导致 早期有益于心脏肥大，后来有益于心力衰竭。 IGF-1 给药可诱导 肥厚并阻止心脏细胞凋亡；然而 ANG II 可以激活这两个过程。在心里， 磷脂酰肌醇 (PI) 3-激酶的激活对于 IGF-1 阻止细胞凋亡的能力至关重要。相比之下， Ras/MAP（丝裂原激活蛋白）激酶途径，可由 IGF-1 和 ANG II 激活， 与心脏肥大有关。我们发现代偿性偏心心脏 肥大与这些激酶的激活增强有关；由此改变钾和 ANG II 和 IGF-1 诱导的钙离子通道主要通过 MAP 激酶和 PI 3- 介导 激酶激活。该研究的目标是了解特定下游的生物学作用 信号通路在控制心肌细胞凋亡和肥大中的作用，并描述了 细胞凋亡导致心力衰竭的发展。该研究基于 3 个假设：1) 信号传导 负责 IGF-1 诱导肥大和阻止细胞凋亡能力的途径是不同的； 2） PI 3-激酶的激活解释了 IGF-1 对心肌细胞存活的有益作用； 3) 细胞凋亡 有助于心力衰竭中心脏功能障碍的发展。为了检验这些假设，我们将使用 腺病毒载体在心肌细胞中表达特定信号分子的野生型和突变型。这 长期目标是了解特定信号通路在心肌细胞凋亡和 开发通过体细胞基因转移局部调节这些途径的方法；这可能 为许多临床重要疾病的管理提供新的治疗方法。