Toba Hiroe, de Castro Brás Lisandra E, Baicu Catalin F, Zile Michael R, Lindsey Merry L, Bradshaw Amy D
Mississippi Center for Heart Research and San Antonio Cardiovascular Proteomics Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi; Department of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan;
Mississippi Center for Heart Research and San Antonio Cardiovascular Proteomics Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi; Department of Physiology, East Carolina University, Greenville, North Carolina;
Am J Physiol Cell Physiol. 2015 Jun 15;308(12):C972-82. doi: 10.1152/ajpcell.00402.2014. Epub 2015 Apr 15.
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.
为了研究富含半胱氨酸的酸性分泌蛋白（SPARC）在年龄相关性心脏炎症中的作用，我们研究了六组小鼠：年轻（3 - 5月龄）、中年（10 - 12月龄）和老年（18 - 29月龄）的C57BL/6野生型（WT）和SPARC基因敲除（Null）小鼠（每组n = 7 - 10只）。通过超声心动图测定心脏功能和结构。取左心室进行细胞因子基因芯片分析，并通过免疫组织化学进行巨噬细胞定量。WT小鼠中巨噬细胞浸润随年龄增加（每组n = 5 - 6只，年轻与老年相比P < 0.05），但在Null小鼠中未出现这种情况。促炎标志物（Ccl5、Cx3cl1、Ccr2和Cxcr3）在中年和老年WT小鼠中增加，而与各自的年轻小鼠相比，仅在老年Null小鼠中增加（每组n = 5 - 6只，所有比较P < 0.05）。这些结果表明，SPARC基因敲除延缓了年龄相关性心脏炎症。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处理增加了促炎巨噬细胞M1标志物的表达，并降低了抗炎M2标志物的表达。超声心动图（每组n = 7 - 10只）显示，WT小鼠左心室壁厚度随年龄增加（年轻小鼠为0.76±0.02 mm，老年小鼠为0.91±0.03 mm；P < 0.05），但在Null小鼠中未出现这种情况（年轻小鼠为0.78±0.01 mm，老年小鼠为0.84±0.02 mm）。总之，SPARC基因敲除在体内和体外均延缓了年龄相关性巨噬细胞浸润增加和促炎细胞因子表达增加。SPARC通过增加巨噬细胞M1标志物的表达和降低M2标志物的表达，作为年龄相关性心脏炎症的重要介质。
