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）：动脉僵硬是衰老的标志，是心血管疾病的胆固醇独立的危险因素，但是如何以及为什么动脉僵硬仍然很大。此处介绍的初步研究揭示了对年龄依赖性动脉僵硬机制及其与动脉粥样硬化的联系的新见解。我们表明，在Apoe-Null和LDLR-Null小鼠中都加速了动脉僵硬，并且这种僵硬是 与VSMC和巨噬细胞中MMP12的表达相关。此外，我们表明性别对生殖年龄女性动脉僵硬和动脉粥样硬化的保护作用与雌激素介导的巨噬细胞MMP12基因表达的抑制有关。值得注意的是，MMP12的缺失足以防止动脉僵硬，并消除了男性性别偏见以及动脉僵硬和动脉粥样硬化。基于这些数据，我们假设衰老，动脉僵硬，性别和动脉粥样硬化之间的联系都可以通过阻止MMP12的表达或活性来打破。此外，我们扩展了最近发表的工作，得出结论，COX2抑制了包括胶原蛋白I的ECM基因的表达，并且这种作用反对动脉僵硬。我们建议COX2抵消MMP12的僵硬作用，并且COX2和MMP12的相互效应在确定整体动脉刚度中起着核心作用。 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.