Aging, gender and arterial stiffness in atherosclerosis

动脉粥样硬化中的衰老、性别和动脉僵硬度

• 批准号: 9268535
• 负责人: Richard Assoian
• 金额: $ 43.94万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268535
• 关键词: Acute; Adoptive Transfer; Affect; Age; Aging; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Blood; Bone Marrow; Cardiovascular Diseases; Cholesterol; Collagen; Data; Development; Disease; Disease Progression; Epoprostenol; Estrogen Replacements; Estrogens; Event; Extracellular Matrix; Female; Gender; Gene Expression; Gene Proteins; Genes; Goals; Hematopoietic; Homing; Intervention; Knockout Mice; Link; MME gene; Mediating; Mus; Nature; Ovariectomy; Pathway interactions; Pharmacology; Phase; Phenocopy; Play; Protein-Lysine 6-Oxidase; Publishing; Role; Sex Bias; Testing; Time; Up-Regulation; Woman; Work; age effect; age related; arterial stiffness; base; cardiovascular risk factor; crosslink; inhibitor/antagonist; insight; macrophage; male; novel; premature; prevent; protective effect; public health relevance; reproductive

DESCRIPTION (provided by applicant): Arterial stiffening is a hallmark of aging and a cholesterol-independent risk factor for cardiovascular disease, but how and why arteries stiffen remain largely unknown. Preliminary studies presented here reveal new insights into the mechanisms of age-dependent arterial stiffening and its link to atherosclerosis. We show that arterial stiffening is accelerated in both apoE-null and LDLR-null mice and that this stiffening is associated with the expression of MMP12 in VSMCs and macrophages. Additionally, we show that the protective effect of gender on arterial stiffness and atherosclerosis in reproductive-age females is associated with an estrogen- mediated inhibition of macrophage MMP12 gene expression. Remarkably, deletion of MMP12 is sufficient to prevent arterial stiffening and eliminate the male gender bias for both arterial stiffening and atherosclerosis. Based on these data, we hypothesize that the links between aging, arterial stiffening, gender, and atherosclerosis can all be broken by blocking the expression or activity of MMP12. Additionally, we extend our recently published work concluding that Cox2 suppresses the expression of ECM genes, including collagen-I, and that this effect opposes arterial stiffening. We propose that Cox2 counteracts the stiffening effect of MMP12, and that the reciprocal effects of Cox2 and MMP12 play central roles in determining overall arterial stiffness. To test these hypotheses, we now propose three aims to: i) define the relationship between MMP12 and arterial stiffening in atherosclerosis, ii) establish the role of age, female gender and estrogen on arterial stiffness, MMP12 expression, and macrophage homing to vessel, and iii) study the functional interactions between Cox2 and MMP12 on arterial stiffening and atherosclerosis.

描述（由申请人提供）：动脉硬化是衰老的标志，也是心血管疾病的独立于胆固醇的危险因素，但动脉硬化的方式和原因仍然很大程度上未知。本文提出的初步研究揭示了对年龄依赖性动脉硬化机制及其与动脉粥样硬化的联系的新见解。我们发现，apoE 缺失和 LDLR 缺失小鼠的动脉硬化都会加速，并且这种硬化是 与 VSMC 和巨噬细胞中 MMP12 的表达相关。此外，我们发现性别对育龄女性动脉僵硬度和动脉粥样硬化的保护作用与雌激素介导的巨噬细胞 MMP12 基因表达抑制有关。值得注意的是，MMP12 的缺失足以预防动脉硬化并消除动脉硬化和动脉粥样硬化的男性性别偏见。基于这些数据，我们假设衰老、动脉硬化、性别和动脉粥样硬化之间的联系都可以通过阻断 MMP12 的表达或活性来打破。此外，我们扩展了最近发表的研究成果，得出结论：Cox2 抑制 ECM 基因（包括 I 型胶原）的表达，并且这种作用可以对抗动脉硬化。我们认为 Cox2 抵消了 MMP12 的硬化效应，并且 Cox2 和 MMP12 的相互作用在确定整体动脉僵硬度方面发挥着核心作用。为了检验这些假设，我们现在提出三个目标：i) 定义 MMP12 与动脉粥样硬化中动脉硬化之间的关系，ii) 确定年龄、女性性别和雌激素对动脉硬化、MMP12 表达和巨噬细胞归巢至血管的作用， iii) 研究 Cox2 和 MMP12 在动脉硬化和动脉粥样硬化中的功能相互作用。