Cardiovascular protection in females linked to estrogen-dependent inhibition of arterial stiffening and macrophage MMP12
Cardiovascular protection in females linked to estrogen-dependent inhibition of arterial stiffening and macrophage MMP12
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DOI：
10.1172/jci.insight.122742
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发表时间：
2019-01-10
期刊：
影响因子：
8
通讯作者：
Assoian, Richard K.
中科院分区：
文献类型：
--
作者：
Liu, Shu-lin;Bajpai, Anamika;Assoian, Richard K.
动脉硬化是衰老的结果，也是心血管疾病（CVD）的非胆固醇依赖性风险因素。动脉硬化和CVD显示出性别偏见，男性比绝经前女性更容易受到影响。动脉僵硬度和性别如何在分子水平上相互作用以赋予CVD的风险尚不清楚。在此，我们利用LDLR基因敲除小鼠的性别二型性来证明雌性对动脉粥样硬化的保护作用与主动脉僵硬度降低和病变巨噬细胞基质金属蛋白酶12（MMP 12）表达减少有关。在LDL受体缺失小鼠中，MMP 12的缺失减弱了动脉硬化和动脉粥样硬化的男性性别偏见，尽管血清胆固醇高，这些影响仍然存在。从机制上讲，我们发现氧化LDL刺激人类以及小鼠巨噬细胞分泌MMP 12。雌激素通过下调MMP 12的表达来拮抗这种作用。我们的数据支持雌激素、氧化LDL诱导的巨噬细胞MMP 12分泌和动脉僵硬度之间的非胆固醇依赖性因果关系，这些因素可保护女性免受动脉粥样硬化，并强调MMP 12功能降低可保护男性免受动脉粥样硬化。
Arterial stiffening is a consequence of aging and a cholesterol-independent risk factor for cardiovascular disease (CVD). Arterial stiffening and CVD show a sex bias, with men more susceptible than premenopausal women. How arterial stiffness and sex interact at a molecular level to confer risk of CVD is not well understood. Here, we used the sexual dimorphism in LDLR-null mice to show that the protective effect of female sex on atherosclerosis is linked to reduced aortic stiffness and reduced expression of matrix metalloproteinase-12 (MMP12) by lesional macrophages. Deletion of MMP12 in LDLR-null mice attenuated the male sex bias for both arterial stiffness and atherosclerosis, and these effects occurred despite high serum cholesterol. Mechanistically, we found that oxidized LDL stimulates secretion of MMP12 in human as well as mouse macrophages. Estrogen antagonizes this effect by downregulating MMP12 expression. Our data support cholesterol-independent causal relationships between estrogen, oxidized LDL-induced secretion of macrophage MMP12, and arterial stiffness that protect against atherosclerosis in females and emphasize that reduced MMP12 functionality can confer atheroprotection to males.