PPAR-gamma Deacetylation in Cardiometabolic Disease

摘要 降低2型动脉粥样硬化性心血管（CV）疾病的发生率、严重程度和并发症 糖尿病仍然是一个关键的未满足的医疗需求。胰岛素抵抗易导致动脉粥样硬化， 2型糖尿病患者的大血管并发症。虽然新的抗高血糖药物 尽管降低糖尿病患者CV事件风险的希望渺茫，但相对疾病负担仍然很大。因此，在本发明中， 需要解决糖尿病发病机理的其它方面，最显著的是胰岛素抗性的治疗。 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， 噻唑烷二酮（TZD）胰岛素增敏剂吡格列酮可降低脑血管事件的复发风险， 近期发生缺血性卒中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恶化、骨折和 膀胱癌在PPG支持的研究中，Accili和Qiang博士表明TZD调节了 通过将两个氨基酸残基K268和K293脱乙酰化来发挥其靶PPARg的功能。他们证明 TZD依赖的PPARg去乙酰化调节后者激活或抑制靶基因的能力。在 初步数据显示，PPARg基因敲入的小鼠纯合，导致其组成性 去乙酰化（K268 R和K293 R，因此为2KR）维持对罗格列酮的胰岛素增敏反应 治疗，但不显示降低骨密度，或增加液体潴留和心率。进一步 他们与塔巴斯和Tall博士合作，发现2KR小鼠的动脉粥样硬化斑块形成减少 与WT相比，在2KR巨噬细胞中，过表达PCSK 9和巨噬细胞增多。法律与正义党 假设，当在Ldlr-/-背景下转移时，2KR突变体PPARg将（a）减少 斑块形成，（B）减少TZD治疗对骨丢失、心脏肥大和体液的不利影响 平衡，和（c）促进用TZD治疗的具有已建立病变的动物中的动脉粥样硬化消退。到 为了验证这一假设，他们将：在目标1中研究2KR突变对动脉粥样硬化进展的影响， 使用与Ldl受体敲除小鼠（Ldlr-/-）杂交的回归，随后进行骨髓移植， 确定预期保护效果的主要部位。他们还将检查2KR-Ldlr-/-小鼠是否 避免罗格列酮的副作用。在目标2中，他们将研究2KR在巨噬细胞功能中的作用， 重点关注红细胞增多症（塔巴斯合作）和胆固醇流出（Tall合作）;在目标3中，他们将 寻求通过基因表达与基因表达相结合的综合方法来确定2KR作用的关键介质， 巨噬细胞中的全基因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.