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）是一种无症状的疾病，如果破裂，死亡率很高（65%至85%） 发生。手术修复是唯一有效的治疗方法，但仅限于合格患者（约占总数的10%）。没有 已经确定了有效的药理学方法来限制AAA进展和破裂。男性是一种 AAA的重要危险因素，男女患病率比约为4-6：1。这种性行为的原因 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。给予雌激素对AAA有保护作用 通过减少促炎介质和蛋白水解途径来改善动物模型。然而，长期以来- 长期雌激素疗法由于不希望的副作用而不能广泛应用于治疗AAA患者。人类 遗传学研究发现，Kruppel样因子14（KLF 14）与慢性代谢相关， 有性别差异的疾病我们以前报道了KLF 14及其激活剂的生物学功能， 哌克西林，临床上用于治疗心绞痛和心力衰竭，在脂质代谢方面表现出较强的 KLF 14的抗炎作用。我们在此描述的初步数据确定巨噬细胞- 选择性Klf 14基因敲除小鼠在雌性中显示出显著增加的AAA发病率， 男性中的那些，表明雌激素/ERα/β通路的保护作用受损。除了抑制 KLF 14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 KLF 14的表达，而KLF 14反过来又是一个关键的转录因子， 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回路。 Perhexiline以KLF 14依赖的方式增加ERα/β水平。一种胆固醇代谢物，24- 羟基胆固醇（24 HC）作为内源性ERα/β激动剂分子发挥作用，并增强抗- 哌克西林对巨噬细胞炎性作用最重要的是，给予哌克西林显著 减少AAA夹层/破裂，增加雄性小鼠的存活率。根据我们的初步发现， 拟议的项目将检验KLF 14防止AAA发展/剥离的中心假设 通过抑制炎症和增强巨噬细胞中ERα/β依赖的保护作用，的 具体目标是：1）确定巨噬细胞KLF 14是AAA小鼠性别差异的重要调节因子 2）确定KLF 14如何调节雌激素/ER s通路，该通路有助于性别二态性 对AAA的保护作用;和3）确定KLF 14的激活抑制AAA的发展/夹层/破裂， AAA小鼠模型。基于KLF 14在AAA中的性别特异性功能，本研究将为进一步研究KLF 14在AAA中的作用机制提供理论依据。 KLF 14作为一个新的治疗靶点，为KLF 14的临床应用奠定了坚实的基础。 KLF 14激活剂，如perhexiline，作为AAA的可行药物治疗，具有改变电流的潜力 AAA的治疗模式。