Multi-analyte profiling reveals matrix metalloproteinase-9 and monocyte chemotactic protein-1 as plasma biomarkers of cardiac aging.
Multi-analyte profiling reveals matrix metalloproteinase-9 and monocyte chemotactic protein-1 as plasma biomarkers of cardiac aging.
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多分析物分析揭示了基质金属蛋白酶-9和单核细胞趋化蛋白-1作为心脏衰老的血浆生物标志物。
DOI：
10.1161/circgenetics.111.959981
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发表时间：
2011-08-01
期刊：
影响因子：
--
通讯作者：
Jin YF
中科院分区：
文献类型：
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作者：
Chiao YA;Dai Q;Zhang J;Lin J;Lopez EF;Ahuja SS;Chou YM;Lindsey ML;Jin YF
我们之前已经证明，在C57/BL6J小鼠中，随着年龄的增长，心脏石棺减少会发生。然而，心脏老化的潜在机制和血浆生物标志物尚未确定。因此，这项研究的目的是识别和评估反映心脏老化表型的血浆生物标志物。收集成年(7.5±0.5月龄，n=27)和衰老(31.7±0.5月龄，n=25)C57/BL6J小鼠的血浆，用多分析方法检测69种标志物的水平。其中，与成年组相比，老年组26个分析物显著增加，3个分析物显著减少。老年组升高的主要是与巨噬细胞功能相关的炎性标志物，包括基质金属蛋白酶-9(MMP9)和单核细胞趋化蛋白-1(MCP-1/CCL-2)。免疫印迹法(n=12/组)显示衰老小鼠左心室(LV)中的MMP9和MCP-1水平升高(P<；0.05)，其表达水平与血浆水平呈正相关(Rho=0.50，Rho=0.62，P<；0.05)。此外，随着年龄的增长，血浆MCP-1和MMP-9水平的增加与舒张末内径的增加相关。巨噬细胞标记物Mac-3的免疫组织化学(n=3/组)显示衰老左室巨噬细胞密度增加；Mac-3和MMP9双重标记免疫组织化学显示MMP9与衰老LV的巨噬细胞共定位，提示巨噬细胞是衰老LV中MMP9的主要来源。我们的结果提示，MCP-1和MMP9可能是心脏老化的潜在血浆标志物，左室内MCP-1和MMP9水平和巨噬细胞含量的增加可能是心脏老化的潜在炎症机制。
We have previously shown that cardiac sarcopenia occurs with age in C57/BL6J mice. However, underlying mechanisms and plasma biomarkers of cardiac aging have not been identified. Accordingly, the objective of this study was to identify and evaluate plasma biomarkers that reflect cardiac aging phenotypes. Plasma from adult (7.5±0.5 months old, n=27) and senescent (31.7±0.5 months old, n=25) C57/BL6J mice was collected and levels of 69 markers were measured by multi-analyte profiling. Of these, 26 analytes were significantly increased and 3 were significantly decreased in the senescent group compared to the adult group. The majority of analytes that increased in the senescent group were inflammatory markers associated with macrophage functions, including matrix metalloproteinase-9 (MMP-9) and monocyte chemotactic protein-1 (MCP-1/CCL-2). Immunoblotting (n=12/ group) showed higher MMP-9 and MCP-1 levels in the left ventricle (LV) of senescent mice (p<0.05), and their expression levels in the LV correlated with plasma levels (rho=0.50 for MMP-9 and rho=0.62 for MCP1, p<0.05). Further, increased plasma MCP-1 and MMP-9 levels correlated with the increase in end diastolic dimensions that occurs with senescence. Immunohistochemistry (n=3/ group) for Mac-3, a macrophage marker, showed increased macrophage densities in the senescent LV; and dual labeling immunohistochemistry of Mac-3 and MMP-9 revealed robust co-localization of MMP-9 to the macrophages in the senescent LV sections, indicating that the macrophage is a major contributor of MMP-9 in the senescent LV. Our results suggest that MCP-1 and MMP-9 are potential plasma markers for cardiac aging and that augmented MCP-1 and MMP-9 levels and macrophage content in the LV could provide an underlying inflammatory mechanism of cardiac aging.