Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization
Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization
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DOI：
10.1152/ajpcell.00402.2014
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发表时间：
2015-06-15
影响因子：
5.5
通讯作者：
Bradshaw, Amy D.
中科院分区：
文献类型：
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作者：
Toba, Hiroe;Bras, Lisandra E. de Castro;Bradshaw, Amy D.
为了研究酸性和富含半胱氨酸的分泌蛋白（SPARC）在年龄相关性心脏炎症中的作用，我们研究了六组小鼠：幼年（3-5月龄）、中年（10-12月龄）和老年（18-29月龄）C57BL/6野生型（WT）和SPARC- Null （Null）小鼠（n = 7-10/组）。超声心动图检测心脏功能及结构。左心室细胞因子基因阵列和巨噬细胞免疫组化定量。巨噬细胞浸润在WT中随年龄增加而增加（n = 5-6/组，年轻组与老年组相比P < 0.05），而在Null中则没有。促炎标志物（Ccl5、Cx3cl1、Ccr2和Cxcr3）在中老年WT中升高，而仅在老年WT中升高（n = 5-6/组，P < 0.05）。这些结果表明SPARC缺失延迟了与年龄相关的心脏炎症。为了进一步评估SPARC如何影响炎症，我们用SPARC刺激腹腔巨噬细胞（n = 4）。SPARC治疗增加了促炎巨噬细胞M1标志物的表达，降低了抗炎M2标志物的表达。超声心动图（n = 7-10/组）显示，WT患者左心室壁厚与年龄相关（年轻组0.76 +/- 0.02 mm，老年组0.91 +/- 0.03 mm; P < 0.05），但Null患者无年龄相关（年轻组0.78 +/- 0.01 mm，老年组0.84 +/- 0.02 mm）。综上所述，SPARC缺失延缓了体内和体外巨噬细胞浸润和促炎细胞因子表达的年龄相关性增加。SPARC通过增加巨噬细胞M1标记物的表达和降低M2标记物的表达，作为与年龄相关的心脏炎症的重要介质。
To investigate the role of secreted protein acidic and rich in cysteine (SPARC) in age-related cardiac inflammation, we studied six groups of mice: young (3-5 mo old), middle-aged (10-12 mo old), and old (18-29 mo old) C57BL/6 wild-type (WT) and SPARC-null (Null) mice (n = 7-10/group). Cardiac function and structure were determined by echocardiography. The left ventricle was used for cytokine gene array and macrophage quantification by immunohistochemistry. Macrophage infiltration increased with age in WT (n = 5-6/group, P < 0.05 for young vs. old), but not in Null. Proinflammatory markers (Ccl5, Cx3cl1, Ccr2, and Cxcr3) increased in middle-aged and old WT, whereas they were increased only in old Null compared with respective young (n = 5-6/group, P < 0.05 for all). These results suggest that SPARC deletion delayed age-related cardiac inflammation. To further assess how SPARC affects inflammation, we stimulated peritoneal macrophages with SPARC (n = 4). SPARC treatment increased expression of proinflammatory macrophage M1 markers and decreased anti-inflammatory M2 markers. Echocardiography (n = 7-10/group) revealed an age-related increase in wall thickness of the left ventricle in WT (0.76 +/- 0.02 mm in young vs. 0.91 +/- 0.03 mm in old; P < 0.05) but not in Null (0.78 +/- 0.01 mm in young vs. 0.84 +/- 0.02 mm in old). In conclusion, SPARC deletion delayed age-related increases in macrophage infiltration and proinflammatory cytokine expression in vivo and in vitro. SPARC acts as an important mediator of age-related cardiac inflammation by increasing the expression of macrophage M1 markers and decreasing M2 markers.