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意义，在这些患者中心力衰竭的发生率很高。高血糖作为一种独立的危险因素，直接导致心脏损害，导致糖尿病心肌病。除了DM诱导的心脏重塑的机制外，从代偿性心肌病到心力衰竭的转变还知之甚少。已有研究表明，DM还影响维生素A的代谢利用率。激活RXR介导的信号通路可改善2型DM的胰岛素抵抗，提示RA信号参与了DM的发生发展。糖尿病患者RAS活性升高与心脏重塑进展及预后不良有关。使用血管紧张素转换酶(ACE)抑制剂(ACEI)和AT1R阻滞剂(ARB)抑制RAS已被证明可以减少心血管事件。然而，用单一位点的抑制剂阻断RAS，往往不能达到完全和持久的药理阻断。在AT1R阻断期间，Ang II的产生保持不受对抗，并为刺激其他Ang II受体108留下了可能性。血管紧张素转换酶抑制剂可能不能完全抑制血管紧张素转换酶II的产生，因为血管紧张素转换酶II的产生存在不依赖于血管紧张素转换酶的机制。我们最近证实，RA抑制肥大刺激诱导的血管紧张素Ⅱ的产生和心脏肾素、血管紧张素转换酶、血管紧张素转换酶和血管紧张素Ⅱ受体的表达，并上调血管紧张素转换酶2的表达。通过抑制RAS级联中的限速步骤，RA可能比ACEI和ARB具有优势。我们的数据表明，RA抑制高血糖诱导的心肌细胞生长、凋亡和细胞内ROS的产生。高糖诱导KLF5表达及核转位可被RA阻断。这些观察结果非常重要，因为KLF5作为核因子-βB的上游介质，已被证明参与血管紧张素转换酶II和压力超负荷诱导的心脏重构。此外，KLF家族成员已被发现与2型糖尿病有关。一种成立的假说是，糖尿病心脏中RA信号的异常表达和/或激活与氧化应激增加、RAS组分的表达增强以及KLF5/NF-1B介导的信号激活有关。靶向激活RA信号可能通过减少氧化应激和抑制RAS组分及其相关信号的表达来阻止DM诱导的心脏重构的发展。我们建议使用体外培养的新生心肌细胞、成纤维细胞和体内的Zucker糖尿病肥胖大鼠，研究DM对RA信号表达/激活的影响，探讨RA介导的信号在DM诱导的心脏重构中的分子机制，并确定RA信号对DM诱导的RAS组分表达/激活的调节机制。识别RA信号的特定分子机制，参与DM介导的细胞效应，可能为开发DM患者和相关心脏并发症的改进治疗提供一种替代途径。公共卫生相关性：我们的建议侧重于确定维甲酸受体介导的信号调节糖尿病诱导的心脏重构的分子机制。这可能导致开发预防和治疗心脏相关糖尿病并发症的新策略。