Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence
Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence
复制标题
DOI：
10.1093/cvr/cvv128
复制
发表时间：
2015-06-01
影响因子：
10.8
通讯作者：
Jin, Yu-Fang
中科院分区：
文献类型：
--
作者：
Ma, Yonggang;Chiao, Ying Ann;Jin, Yu-Fang
目的心脏衰老涉及由基质金属蛋白酶-9调节的心肌纤维化和舒张期功能障碍的渐进性发展。方法和结果对C57BL/6J野生型(WT)和基质金属蛋白酶-9缺失的年轻(6-9个月)、中年(12-15个月)、老年(18-24个月)和衰老(26-34个月)的小鼠进行了评估。使用已识别的炎症模式，我们能够基于它们的生物学年龄而不是时间上的年龄来定义单个小鼠。Bcl6、Ccl24和IL4是心脏老化征象中最强的炎症标志物。Bcl6、IL1r1、Ccl24、CRP和CXCL13模式对早期和晚期LV充盈率下降的预测作用最强，而Abcf1、Tollip、Scye1和Mif模式对LV壁厚度的预测作用最强。随着年龄的增长，WT小鼠心脏M1巨噬细胞呈线性增加，而心脏M2巨噬细胞减少；两者均被基质金属蛋白酶-9缺失所阻止。在体外，基质金属蛋白酶-9直接激活年轻巨噬细胞极化到M1/M2中间过渡状态。结论我们的结果明确了心脏老化的炎症特征，并指定基质金属蛋白酶-9通过间接和直接改变巨噬细胞极化在介导炎症过程中的作用。我们的结果解释了刺激衰老诱导的心脏纤维化和舒张期功能障碍的早期机制。
Aims Cardiac ageing involves the progressive development of cardiac fibrosis and diastolic dysfunction coordinated by MMP-9. Here, we report a cardiac ageing signature that encompasses macrophage pro-inflammatory signalling in the left ventricle (LV) and distinguishes biological from chronological ageing.Methods and results Young (6-9 months), middle-aged (12-15 months), old (18-24 months), and senescent (26-34 months) mice of both C57BL/6J wild type (WT) and MMP-9 null were evaluated. Using an identified inflammatory pattern, we were able to define individual mice based on their biological, rather than chronological, age. Bcl6, Ccl24, and Il4 were the strongest inflammatory markers of the cardiac ageing signature. The decline in early-to-late LV filling ratio was most strongly predicted by Bcl6, Il1r1, Ccl24, Crp, and Cxcl13 patterns, whereas LV wall thickness was most predicted by Abcf1, Tollip, Scye1, and Mif patterns. With age, there was a linear increase in cardiac M1 macrophages and a decrease in cardiac M2 macrophages in WT mice; of which, both were prevented by MMP-9 deletion. In vitro, MMP-9 directly activated young macrophage polarization to an M1/M2 mid-transition state.Conclusion Our results define the cardiac ageing inflammatory signature and assign MMP-9 roles in mediating the inflammaging profile by indirectly and directly modifying macrophage polarization. Our results explain early mechanisms that stimulate ageing-induced cardiac fibrosis and diastolic dysfunction.