Role of Retinoid Mediated Signaling in Diabetes and Cardiac Remodeling

类维生素A介导的信号在糖尿病和心脏重塑中的作用

• 批准号: 7579365
• 负责人: KENNETH Melvin BAKER
• 金额: $ 39.38万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579365
• 关键词: Accounting; Address; Adult; Affect; All-Trans-Retinol; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Animal Model; Antioxidants; Apoptosis; Biological Process; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Cell Survival; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Epidemiology; Event; Family; Fibroblasts; Figs - dietary; G-Protein-Coupled Receptors; Generations; Glucose; Growth; Growth Factor; Heart; Heart Hypertrophy; Heart failure; Hyperglycemia; Impairment; In Vitro; Incidence; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Kidney; Laboratories; Lead; Left; Ligands; Link; MAPK14 gene; MAPK8 gene; Mechanics; Mediating; Mediator of activation protein; Metabolic; Modeling; Molecular; Neonatal; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Translocation; Oxidative Stress; Pathway interactions; Patients; Peptidyl-Dipeptidase A; Phosphotransferases; Plasma; Prevention; Process; Production; Publishing; RXR; Rattus; Reactive Oxygen Species; Regulation; Renin; Renin-Angiotensin System; Reporting; Retinal; Retinoid Receptor; Retinoids; Retinol Binding Proteins; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Site; Stimulus; Stretching; System; Transactivation; Tretinoin; Up-Regulation; Vitamin A; cell growth; diabetic; diabetic cardiomyopathy; diabetic patient; diabetic rat; improved; in vivo; in vivo Model; inhibitor/antagonist; lipid biosynthesis; member; novel strategies; outcome forecast; oxidative damage; pressure; prevent; protective effect; public health relevance; receptor; receptor-mediated signaling; response

DESCRIPTION (provided by applicant): Diabetes mellitus (DM) is of major epidemiological importance, accounting for a high incidence of heart failure in these patients. Hyperglycemia, as an independent risk factor, directly causes cardiac damage and leads to diabetic cardiomyopathy. Apart from the mechanisms of DM-induced cardiac remodeling, little is known about the transition from compensated cardiomyopathy to heart failure. It has been shown that DM also affects the metabolic availability of vitamin A. Activation of RXR-mediated signaling improves insulin resistance in type 2 DM, indicating that RA signaling is involved in the development of DM. Elevated activity of the RAS is associated with progression of cardiac remodeling and a poor prognosis in patients with DM. Suppression of the RAS, using angiotensin converting enzyme (ACE) inhibitors (ACEI) and AT1R blockers (ARBS), has been shown to reduce cardiovascular events. However, interrupting the RAS with a single-site inhibitor, often does not achieve complete and long-lasting pharmacological blockade. The generation of Ang II remains unopposed during AT1R-blockade and leaves the potential for stimulation of other Ang II receptors108. ACE inhibitors may not suppress the production of Ang II completely, since there are ACE-independent mechanisms for Ang II production. We have recently demonstrated that RA suppresses hypertrophic stimuli-induced production of Ang II and cardiac expression of renin, Ao, ACE and AT1R and upregulates the expression of ACE2. By inhibiting the rate-limiting step in the RAS cascade, RA might have advantages over ACEI and ARBs. Our data demonstrate that RA suppresses hyperglycemia induced cardiomyocyte growth, apoptosis, and intracellular ROS generation. High-glucose induced expression of Kruppel-like factor 5 (KLF5) and nuclear translocation of NF-?B was blocked by RA. These observations are extremely important in that KLF5, as an upstream mediator of NF-?B, has been demonstrated to be involved in both Ang II and pressure-overload induced cardiac remodeling. Additionally, members of the KLF family have been found to be involved in Type 2 DM. A tenable hypothesis is that abnormal expression and/or activation of RA signaling in the diabetic heart is associated with increased oxidative stress, enhanced expression of RAS components and activation of KLF5/NF-?B mediated signaling. Targeted activation of RA signaling may prevent DM-induced development of cardiac remodeling, by reducing oxidative stress and through inhibition of expression of RAS components and associated signaling. We propose using in vitro cultured neonatal cardiac myocytes and fibroblasts and in vivo Zucker Diabetic Fatty rats, to determine the effect of DM on the expression/activation of RA signaling, address the molecular mechanisms of RA-mediated signaling in DM-induced cardiac remodeling and determine the regulatory mechanisms of RA signaling on DM-induced expression/activation of RAS components. Identifying the specific molecular mechanisms of RA signaling, involved in DM-mediated cellular effects, may provide an alternative approach for developing improved therapies for patients with DM and related cardiac complications. PUBLIC HEALTH RELEVANCE: Our proposal focuses on determining the molecular mechanisms whereby retinoid receptor-mediated signaling regulates diabetes mellitus-induced cardiac remodeling. This may lead to the development of novel strategies for the prevention and treatment of cardiac related diabetic complications.

描述（由申请人提供）：糖尿病（DM）具有重要的流行病学重要性，是这些患者心力衰竭发病率较高的原因。高血糖作为独立危险因素，直接造成心脏损害，导致糖尿病心肌病。除了糖尿病引起的心脏重塑的机制外，人们对代偿性心肌病向心力衰竭的转变知之甚少。研究表明，DM 还会影响维生素 A 的代谢利用率。RXR 介导的信号传导的激活可改善 2 型 DM 的胰岛素抵抗，表明 RA 信号传导参与了 DM 的发展。 RAS 活性升高与糖尿病患者心脏重塑的进展和不良预后相关。使用血管紧张素转换酶 (ACE) 抑制剂 (ACEI) 和 AT1R 阻滞剂 (ARBS) 抑制 RAS 已被证明可以减少心血管事件。然而，用单位点抑制剂中断 RAS 通常无法实现完全且持久的药理封锁。 AT1R 阻断期间，Ang II 的生成仍然不受阻碍，并有可能刺激其他 Ang II 受体108。 ACE 抑制剂可能无法完全抑制 Ang II 的产生，因为 Ang II 的产生存在不依赖于 ACE 的机制。我们最近证明，RA 可以抑制肥大刺激诱导的 Ang II 产生和心脏肾素、Ao、ACE 和 AT1R 的表达，并上调 ACE2 的表达。通过抑制 RAS 级联中的限速步骤，RA 可能比 ACEI 和 ARB 更具优势。我们的数据表明，RA 抑制高血糖诱导的心肌细胞生长、细胞凋亡和细胞内 ROS 生成。高糖诱导的 Kruppel 样因子 5 (KLF5) 表达和 NF-κB 核转位被 RA 阻断。这些观察结果极其重要，因为 KLF5 作为 NF-κB 的上游介质，已被证明参与 Ang II 和压力过载诱导的心脏重塑。此外，KLF 家族的成员被发现与 2 型糖尿病有关。一个成立的假设是，糖尿病心脏中 RA 信号传导的异常表达和/或激活与氧化应激增加、RAS 成分表达增强以及 KLF5/NF-κB 介导的信号传导激活有关。 RA 信号传导的靶向激活可以通过减少氧化应激以及抑制 RAS 成分和相关信号传导的表达来预防 DM 诱导的心脏重塑的发展。我们建议使用体外培养的新生心肌细胞和成纤维细胞以及体内 Zucker 糖尿病脂肪大鼠来确定 DM 对 RA 信号表达/激活的影响，解决 RA 介导的信号在 DM 诱导的心脏重塑中的分子机制，并研究确定 RA 信号传导对 DM 诱导的 RAS 成分表达/激活的调节机制。确定参与 DM 介导的细胞效应的 RA 信号传导的具体分子机制，可能为开发针对 DM 和相关心脏并发症患者的改进疗法提供替代方法。公共健康相关性：我们的建议重点是确定类维生素A受体介导的信号传导调节糖尿病引起的心脏重塑的分子机制。这可能会导致开发预防和治疗心脏相关糖尿病并发症的新策略。