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.

腹主动脉瘤 (AAA) 是一种无症状疾病，如果破裂，死亡率很高（65% 至 85%） 手术修复是唯一有效的治疗方法，但仅限于符合条件的患者（约占总数的 10%）。 已确定有效的药理学方法来限制 AAA 的进展和破裂。 AAA的重要危险因素，男女患病比例约为4-6:1，原因是这种性别。 差异尚不清楚，但女性 AAA 的延迟发作表明雌激素及其受体 (ER) 可能在降低 AAA 患病率方面发挥作用，雌激素对 AAA 具有保护作用。 通过减少促炎介质和蛋白水解途径来建立动物模型。 由于不良副作用，术语雌激素疗法不能广泛应用于治疗 AAA 患者。 遗传学研究发现 Kruppel 样因子 14 (KLF14) 与慢性代谢密切相关 我们之前报道过KLF14及其激活剂的生物学功能， perhexiline，临床上用于治疗心绞痛和心力衰竭，在脂质代谢中表现出强大的作用 我们在此描述的初步数据证实了 KLF14 的抗炎作用。 选择性 Klf14 基因敲除小鼠显示，女性 AAA 发病率显着增加，与 男性中的情况，表明除了抑制作用外，雌激素/ERα/β途径的保护作用也受损。 通过KLF14对炎症反应和MMP-9活性的影响，我们进一步发现雌激素上调 KLF14 的表达，而 KLF14 又是上调 KLF14 表达的关键转录因子 巨噬细胞中的 ERα/β，揭示了可能导致观察到的性别差异的前馈循环。 Perhexiline 以 KLF14 依赖性方式增加 ERα/β 水平，一种胆固醇代谢物 24-。 羟基胆固醇（24HC），作为内源性 ERα/β 激动分子发挥作用，增强抗- 最重要的是，哌克西林对巨噬细胞的炎症作用显着。 根据我们的初步研究结果，减少了 AAA 剥离/破裂并提高了雄性小鼠的存活率。 拟议的项目将测试 KLF14 防止 AAA 发展/解剖的中心假设 /破裂通过抑制炎症和增强巨噬细胞中 ERα/β 依赖性保护作用。 具体目标将 1) 确定巨噬细胞 KLF14 是 AAA 小鼠性别差异的重要调节因子 模型；2) 确定 KLF14 如何调节有助于性别二态性的雌激素/ER 途径 对 AAA 的保护作用；3) 确定 KLF14 的激活抑制 AAA 的发育/解剖/破裂 AAA小鼠模型基于KLF14在AAA中的性别特异性功能，该机制研究将 确立KLF14作为新的治疗靶点，将为临床应用奠定坚实的基础 KLF14 激活剂，如哌克西林，作为 AAA 的可行药物治疗，有可能改变目前的治疗方法 AAA 的治疗范例。