KLF14 and Cardiovascular Disease

KLF14 与心血管疾病

• 批准号: 10569551
• 负责人: YUQING Eugene CHEN
• 金额: $ 61.86万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569551
• 关键词: Abdominal Aortic Aneurysm; Adult; Animal Model; Antiinflammatory Effect; Aortic Rupture; Biological Process; Cardiovascular Diseases; Cells; ChIP-seq; Cholesterol; Chronic; Chronic Disease; Clinical; Coupled; Data; Dependence; Development; Dilatation - action; Disease; Dissection; Eligibility Determination; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogen Therapy; Estrogens; Female; Foundations; GTP-Binding Proteins; Gelatinase B; Genetic Transcription; Genetic study; Heart failure; Hormones; Human; Human Genetics; Hydroxycholesterols; Impairment; In Vitro; Incidence; Individual; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Knockout Mice; Life; Macrophage; Matrix Metalloproteinases; Mediating; Metabolic Diseases; Mus; Myelogenous; Myeloid Cells; Nuclear; Operative Surgical Procedures; Oral Administration; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Physiological; Prevalence; Prevention therapy; Reporting; Research; Risk Factors; Role; Rupture; Sex Differences; Solid; Survival Rate; Testing; Therapeutic; Time; Transgenic Organisms; Woman; abdominal aorta; effective therapy; gain of function; lipid metabolism; loss of function; male; men; mortality; mouse model; new therapeutic target; p65; pharmacologic; protective effect; receptor; repaired; sex; sex disparity; side effect; transcription factor

Abdominal aortic aneurysm (AAA) is an asymptomatic disease of high mortality rate (65% to 85%) if rupture occurs. Surgical repair is the only effective treatment, but limited to eligible patients (about 10% of total). No effective pharmacological approach has been identified to limit AAA progression and rupture. Male sex is an important risk factor for AAA, with about 4-6:1 male to female prevalence ratio. The reasons for this sex disparity are unknown, but the delayed onset of AAA in women suggests that estrogen and its receptors (ERs) may play a role in reducing the prevalence of AAA. Administration of estrogen has protective effects in AAA animal models through reduction of pro-inflammatory mediators and the proteolytic pathway. However, long- term estrogen therapy cannot be widely applied to treat AAA patients due to undesirable side-effects. Human genetic studies uncovered that Kruppel-like factor 14 (KLF14) is robustly associated with chronic metabolic diseases with a sex difference. We previously reported the biological function of KLF14 and its activator, perhexiline, clinically used to treat angina and heart failure, in lipid metabolism and demonstrate the strong anti-inflammatory effect of KLF14. Our preliminary data described herein established that macrophage- selective Klf14 knockout mice showed significantly increased AAA incidence rates in females, comparable to those in males, suggesting impaired protective effects of estrogen/ERα/β pathway. Besides the inhibitory effects of KLF14 on the inflammatory response and MMP-9 activity, we further found that estrogen upregulates the expression of KLF14 while KLF14, in turn, is a critical transcription factor upregulating the expression of ERα/β in macrophages, uncovering a feedforward loop that may contribute to the observed sex disparity. Perhexiline increased the levels of ERα/β in a KLF14-dependent manner. A cholesterol metabolite, 24- hydroxycholesterol (24HC), functioned as an endogenous ERα/β agonistic molecule and enhanced the anti- inflammatory effect of perhexiline in macrophages. Most importantly, administration of perhexiline significantly reduced AAA dissection/rupture and increased survival rate in male mice. Based on our preliminary findings, the proposed project will test the central hypothesis that KLF14 protects against AAA development/dissection /rupture by suppressing inflammation and enhancing ERα/β-dependent protective roles in macrophages. The specific aims will 1) define that macrophage KLF14 is an important regulator of sex differences in AAA mouse models; 2) determine how KLF14 regulates the estrogen/ERs pathway which contributes to sex-dimorphic protective effects on AAA; and 3) determine that activation of KLF14 inhibits development/dissection/rupture in AAA mouse models. Based on the sex-specific functions of KLF14 in AAA, this mechanistic research will establish KLF14 as a novel therapeutic target and will set a solid foundation towards clinical utilization of KLF14 activators, like perhexiline, as a viable drug therapy for AAA, with the potential to change current treatment paradigms for AAA.

如果破裂，腹部主动脉瘤（AAA）是一种高死亡率的无症状疾病（65％至85％） 发生。手术修复是唯一有效的治疗方法，但仅限于合格的患者（约占总数的10％）。不 已经确定了有效的药理方法以限制AAA的进展和破裂。男性是 AAA的重要危险因素，约4-6：1男性与女性患病率。这种性别的原因 差异是未知的，但是女性AAA的延迟发作表明雌激素及其接收器（ERS） 可能在降低AAA的患病率方面发挥作用。雌激素的给药在AAA中受到保护的影响 动物模型通过减少促炎性介体和蛋白水解途径。但是，长期 由于不良副作用，雌激素治疗术语不能广泛应用于治疗AAA患者。人类 遗传研究发现，Kruppel样因子14（KLF14）与慢性代谢有牢固相关 性别差异的疾病。我们以前报道了KLF14及其激活剂的生物学功能 perhexiline，用于治疗心绞痛和心力衰竭的临床上，在脂质代谢中证明了强烈的 KLF14的抗炎作用。我们所描述的我们的初步数据确定巨噬细胞 - 选择性KLF14敲除小鼠显示出女性的AAA入射率显着提高，可与 在男性中，表明雌激素/ERα/β途径受保护作用受损。除了抑制性 KLF14对炎症反应和MMP-9活性的影响，我们进一步发现雌激素会上调 KLF14的表达反过来，KLF14是上调的关键转录因子 巨噬细胞中的ERα/β，发现可能导致观察到的性别差异的前馈回路。 Perhexiline以KLF14依赖性方式增加了ERα/β的水平。胆固醇代谢物，24- 羟基胆固醇（24HC），充当内源性ERα/β激动剂分子，并增强了抗抗 - perheciline在巨噬细胞中的炎症作用。最重要的是，给药明显 雄性小鼠的AAA解剖/破裂和生存率降低。根据我们的初步发现 拟议的项目将测试KLF14防止AAA开发/解剖的中心假设 /通过抑制注射并增强ERα/β依赖性保护作用来破裂。这 具体目的将1）定义巨噬细胞KLF14是AAA小鼠性别差异的重要调节因子 模型； 2）确定KLF14如何调节雌激素/ERS途径，这有助于性二态 对AAA的保护作用； 3）确定KLF14的激活抑制了开发/解剖/破裂 AAA鼠标模型。根据KLF14在AAA中的性别特异性功能，这项机械研究将 将KLF14建立为一种新型的治疗靶标，并将为临床利用树立坚实的基础 KLF14激活剂，例如Perhexiline，作为AAA的可行药物疗法，有可能改变电流 AAA的治疗范例。