Aging, gender and arterial stiffness in atherosclerosis

描述(申请人提供)：动脉硬化是衰老的一个标志，也是心血管疾病的一个不依赖胆固醇的危险因素，但动脉硬化的原因和原因在很大程度上仍不清楚。这里提出的初步研究揭示了年龄依赖性动脉硬化的机制及其与动脉粥样硬化的联系。我们发现动脉硬化在apoE缺失和LDLR缺失的小鼠中都是加速的，并且这种硬化与VSMCs和巨噬细胞中MMP12的表达有关。此外，我们还表明，性别对育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硬化，并消除男性对动脉硬化和动脉硬化的性别偏见。基于这些数据，我们假设，年龄、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，我们扩展了我们最近发表的工作，得出结论，COX2抑制ECM基因的表达，包括I型胶原，这一效应反对动脉硬化。我们认为，COX2可以抵消MMP12的强直效应，并且COX2和MMP12的相互作用在决定整体动脉僵硬中起着核心作用。为了验证这些假说，我们现在提出三个目标：i)确定动脉硬化中MMP12与动脉硬化的关系；ii)确定年龄、性别和雌激素对动脉硬化、MMP12表达和巨噬细胞归巢到血管中的作用；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。

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.