PPAR-gamma Deacetylation in Cardiometabolic Disease

摘要 降低2型患者动脉粥样硬化性心血管(CV)疾病的发生率、严重性和并发症 糖尿病仍然是一个关键的未得到满足的医疗需求。胰岛素抵抗易患动脉粥样硬化，加重动脉粥样硬化 2型糖尿病患者的大血管并发症。而新的抗高血糖药物提供了 在降低糖尿病心血管事件风险的一线希望下，相对疾病负担仍然很大。因此， 需要针对糖尿病发病机制的其他方面进行治疗，最明显的是胰岛素抵抗。 最近的一项研究表明，胰岛素增敏剂对动脉粥样硬化的影响重新点燃了人们的兴趣。 噻唑烷二酮(TZD)胰岛素增敏剂吡格列酮降低脑血管事件的复发风险 近期发生缺血性中风或短暂性脑缺血发作的胰岛素抵抗患者。然而，使用这些 药物会受到严重不良事件的影响，包括充血性心力衰竭、骨折和 膀胱癌。在这项由PPG支持的研究中，Accili博士和Qiang博士已经证明TZD调节 它们的靶PPARg通过去乙酰化两个氨基酸残基K268和K293发挥作用。他们展示了 依赖TZD的PPARg去乙酰化调节后者激活或抑制靶基因的能力。在……里面 初步数据表明，小鼠的PPARg敲入等位基因纯合导致了它的结构性 去乙酰化(K268R和K293R，即2KR)维持罗格列酮的胰岛素增敏反应 治疗，但不显示骨密度降低，或增加液体滞留和心率。此外，在 与Tabas和Tall博士合作，他们表明2KR小鼠动脉粥样硬化斑块的形成减少 与WT相比，2KR巨噬细胞过度表达PCSK9，吞噬功能明显增强。私人投资促进局 假设，当在Ldlr-/-背景上转移时，2KR突变体PPARg将(A)减少 斑块形成，(B)减少TZD治疗对骨丢失、心肌肥大和液体的不良影响 平衡，以及(C)促进TZD治疗已建立病变的动物的动脉粥样硬化消退。至 验证这一假设，他们将：在目标1研究2KR突变对动脉粥样硬化进展和 与低密度脂蛋白受体基因敲除小鼠(Ldlr-/-)杂交进行回归，随后进行骨髓移植 确定主要部位(S)的预期防护效果。他们还将检查2KR-Ldlr-/-小鼠是否 使其免受罗格列酮的不良影响。在目标2中，他们将研究2KR对巨噬细胞功能的影响， 重点放在胞吐作用(Tabas协作)和胆固醇流出(Tall协作)；在目标3中，他们将 寻求通过基因表达和基因表达相结合的综合方法识别2KR作用的关键介质 巨噬细胞全基因组组蛋白修饰和增强子研究。

ABSTRACT Reducing the incidence, severity, and complications of atherosclerotic cardiovascular (CV) disease in type 2 diabetes remains a key unmet medical need. Insulin resistance predisposes to atherosclerosis and worsens its macrovascular complications in patients with type 2 diabetes. While new anti-hyperglycemic drugs offer glimmers of hope to reduce the risk of CV events in diabetes, the relative disease burden remains large. Thus, treatments that address other aspects of diabetes pathogenesis, most notably insulin resistance, are needed. Interest in the effects of insulin sensitizers on atherosclerosis was rekindled by a recent study showing that the thiazolidinedione (TZD) insulin-sensitizer, pioglitazone, reduced the recurrence risk of cerebrovascular events in insulin-resistant patients with a recent ischemic stroke or transient ischemic attack. However, use of these agents is marred by serious adverse events, including worsening of congestive heart failure, fractures, and bladder cancer. In studies supported by this PPG, Drs. Accili and Qiang have shown that TZDs regulate the function of their target PPARg by deacetylating two amino acid residues, K268 and K293. They demonstrated that TZD-dependent deacetylation of PPARg modulates the latter’s ability to activate or repress target genes. In preliminary data, they show that mice homozygous for knock-in alleles of PPARg resulting in its constitutive deacetylation (K268R and K293R, thus 2KR) maintain the insulin-sensitizing response to rosiglitazone treatment, but don’t show reduced bone density, or increased fluid retention and heart rate. Further, in collaboration with Drs. Tabas and Tall, they show that atherosclerosis plaque formation is reduced in 2KR mice overexpressing PCSK9, and efferocytosis greatly increased in 2KR macrophages compared to WT. The PIs hypothesize that, when transferred on the Ldlr–/– background, the 2KR mutant PPARg will (a) decrease plaque formation, (b) reduce the adverse effects of TZD treatment on bone loss, cardiac hypertrophy, and fluid balance, and (c) promote atherosclerosis regression in animals with established lesions treated with TZD. To test the hypothesis, they will: in Aim 1 study the effect of the 2KR mutation on atherosclerosis progression and regression using crosses with Ldl receptor knockout mice (Ldlr–/–), followed by bone marrow transplants to determine the main site(s) of the expected protective effect. They will also examine whether 2KR-Ldlr–/– mice are protected from rosiglitazone’s adverse effects. In Aim 2 they will study the effect of 2KR in macrophage function, with a focus on efferocytosis (Tabas collaboration) and cholesterol efflux (Tall collaboration); in Aim 3 they will seek to identify the critical mediators of 2KR action by an integrative approach combining gene expression with genome-wide histone modification and enhancer studies in macrophages.