The Role of RNase L in Cardiovascular Diseases

RNase L 在心血管疾病中的作用

• 批准号: 6854416
• 负责人: AIMIN ZHOU
• 金额: $ 13.21万
• 依托单位: CLEVELAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6854416
• 关键词: apoptosis; atherosclerosis; endoribonucleases; enzyme activity; enzyme induction /repression; gene expression; inflammation; laboratory mouse; leukocyte activation /transformation; macrophage; molecular pathology; nitric oxide synthase; northern blottings; nuclear runoff assay; peroxisome proliferator activated receptor; polymerase chain reaction; prostaglandin endoperoxide synthase; protein structure function

DESCRIPTION (provided by applicant): Atherosclerosis defined as a chronic inflammatory disease of large arteries is the primary cause of heart diseases and stroke. Inflammation is a central process in all stages of atherosclerosis. The formation of early atherosclerotic lesions involves the recruitment and activation of immune cells, particularly macrophages. The functions of macrophages play a critical role in the development of atherosclerosis. Although studies have yielded much information about the role of macrophages in atherosclerosis, the molecular basis of macrophage functions, such as the regulatory expression of proinflammatory genes, uptake of oxidized low-density lipoprotein (oxLDL) to form foam cells and apoptosis, remains to be fully understood. 2-5A dependent RNase L (RNase L) is one of the key enzymes involved in the interferon (IFN) functions against viral infection and cell proliferation. Furthermore, the role of RNase L in the regulation of gene expression and cell apoptosis has been well established in the last decade. In this proposed study, we hypothesize that RNase L regulates the macrophage expression of proinflammatory genes induced by different atherogenic stimuli, and modulates macrophage functions, resulting in the promotion of inflammatory response and lesion formation in the process of atherosclerotic development. This hypothesis is based on our preliminary studies that RNase L functions as a regulator for the expression of cyclooxygenase-2 (Cox-2) and peroxisome proliferators-activated receptorgamma (PPAR-y,) in mouse embryonic fibroblasts (MEF). Both genes are involved in the inflammatory process during the development of atherosclerosis. RNase L also mediates bone marrow-derived macrophage apoptosis after withdrawal of M-CSF. To test our hypothesis, the following aims are proposed: (1) To investigate the effect of RNase L on the expression of proinflammatory genes, we will examine the expression of Cox-2, PPAR-y and inducible nitric oxide synthase (iNOS) in RNase L +/+ and -/- bone marrow-derived macrophages stimulated by lipopolysaccharide (LPS), polyinosinic-polycytidylic (Poly I:C) and oxLDL; (2) To determine the role of RNase L in mediating the development of atherosclerotic lesions, we will first determine the role of RNase L in the formation of foam cells and macrophage apoptosis. We will also determine the vulnerability of RNase L null and wild type mice in the development of atherosclerosis. This study will provide new insights into the molecular mechanism of atherosclerotic development.

描述(申请人提供)：动脉粥样硬化定义为大动脉的慢性炎症性疾病，是心脏病和中风的主要原因。炎症是动脉粥样硬化所有阶段的中心过程。早期动脉粥样硬化病变的形成涉及免疫细胞，特别是巨噬细胞的募集和激活。巨噬细胞的功能在动脉粥样硬化的发生发展中起着至关重要的作用。虽然巨噬细胞在动脉粥样硬化中的作用已有大量研究，但巨噬细胞功能的分子基础，如促炎基因的调节表达、氧化低密度脂蛋白(OxLDL)的摄取形成泡沫细胞和细胞凋亡，仍未完全清楚。依赖2-5A的核糖核酸酶L(核糖核酸酶L)是干扰素抗病毒感染和细胞增殖的关键酶之一。此外，核糖核酸酶L在基因表达调控和细胞凋亡中的作用在过去的十年中已经得到了很好的证实。在这项研究中，我们假设核糖核酸酶L调节不同致动脉粥样硬化刺激诱导的巨噬细胞促炎基因的表达，并调节巨噬细胞的功能，从而在动脉粥样硬化发展过程中促进炎症反应和病变的形成。这一假说是基于我们的初步研究，即核糖核酸酶L对小鼠胚胎成纤维细胞环氧合酶-2(COX-2)和过氧化物酶体增殖物激活受体γ(PPAR-y)的表达起调节作用。这两个基因都参与了动脉粥样硬化发展过程中的炎症过程。核糖核酸酶L还介导了停用M-CSF后骨髓源性巨噬细胞的凋亡。为了验证我们的假设，我们提出了以下目标：(1)为了研究核糖核酸酶L对促炎症基因表达的影响，我们将检测核糖核酸酶L+/+和-/-骨髓来源的巨噬细胞在脂多糖、多聚肌苷多胞苷和氧化低密度脂蛋白刺激下，COX-2、PPAR-y和诱导型一氧化氮合酶的表达；(2)为了确定核糖核酸酶L在介导动脉粥样硬化病变发展中的作用，我们将首先确定核糖核酸酶L在泡沫细胞和巨噬细胞凋亡中的作用。我们还将确定核糖核酸酶L缺失型和野生型小鼠在动脉粥样硬化发展中的易感性。这项研究将为动脉粥样硬化发展的分子机制提供新的见解。