Role of Retinoid Mediated Signaling in Diabetes and Cardiac Remodeling

描述（由申请人提供）：糖尿病（DM）具有重要的流行病学意义，是这些患者心力衰竭的高发原因。高血糖作为一个独立的危险因素，直接导致心脏损伤，导致糖尿病性心肌病。除了dm诱导的心脏重塑机制外，对代偿性心肌病向心力衰竭的转变知之甚少。研究表明，糖尿病还会影响维生素a的代谢利用率。rxr介导的信号激活可改善2型糖尿病患者的胰岛素抵抗，表明RA信号参与糖尿病的发展。RAS活性升高与糖尿病患者心脏重构的进展和不良预后相关。已被证明可以减少心血管事件。然而，用单位点抑制剂阻断RAS通常不能实现完全和持久的药物阻断。在at1r阻断期间，Ang II的产生仍然不受反对，并留下了刺激其他Ang II受体的潜力。ACE抑制剂可能不能完全抑制Ang II的产生，因为存在与ACE无关的Ang II产生机制。我们最近证明，RA抑制肥厚刺激诱导的Ang II的产生和肾素、Ao、ACE和AT1R的心脏表达，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kruppel样因子5 （KLF5）表达及NF-？B被RA阻断。这些观察结果非常重要，因为KLF5作为NF-？B，已被证明参与Ang II和压力过载诱导的心脏重构。此外，KLF家族成员已被发现与2型糖尿病有关。一个成立的假设是，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成分表达增强和KLF5/NF-？B介导的信号。RA信号的靶向激活可能通过减少氧化应激和抑制RAS成分及相关信号的表达来阻止dm诱导的心脏重构的发展。我们拟采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，研究DM对RA信号表达/激活的影响，探讨DM诱导的心脏重构中RA介导的信号转导的分子机制，确定RA信号转导对DM诱导的RAS组分表达/激活的调控机制。识别RA信号的特定分子机制，参与DM介导的细胞效应，可能为开发改善糖尿病和相关心脏并发症患者的治疗方法提供另一种方法。公共卫生相关性：我们的建议侧重于确定类视黄醛受体介导的信号调节糖尿病诱导的心脏重构的分子机制。这可能会导致预防和治疗心脏相关糖尿病并发症的新策略的发展。

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.