Progression of Arterial Aging: the Local MCP-1/MMP-2/TGF-beta 1 Signaling Loop

在这项研究中，双重染色显示，MCP-1和TGF-β 1，一种强大的促纤维化细胞因子，显着增加，并共同定位在主动脉壁增厚，内膜的大鼠，非人灵长类动物，和人类与衰老。 心血管信号网络分析表明， MCP-1与TGF-β 1相互作用。 并且位于中心并与炎症级联反应直接相关，炎症级联反应与MMP-2活化密切相关。体外研究表明，MCP-1通过CCR-2信号以剂量或时间依赖性方式升高来自年轻（8个月）大鼠直肠的培养VSMC中的MMP 2，MMP 2是潜伏性TGF-β 1的已知激活剂，达到老年细胞（30个月）的水平。MCP-1处理增加了活化的细胞内和细胞外TGF-β 1及其下游分子I型和III型胶原蛋白， 其依赖于年轻VSMC中MMP-2的活化，达到未处理的老细胞的水平。 随着年龄的增长，细胞活化的TGF-β 1在VSMC胞浆、细胞器和细胞核中的分布逐渐增多。有趣的是，通过siRNA敲低MCP-1或通过腺病毒转染过度表达异位TIMP-2可减少MMP-2和TGF-β 1的活化以及老年VSMC中I型和III型胶原的产生。 此外，MCP-1处理增强了年轻细胞的侵袭能力，MMP-2激活依赖性的方式，类似于未处理的老细胞。CCR-2和MMP抑制剂GM 6001可显著降低这些作用。值得注意的是，TGF-β 1治疗以剂量依赖性方式增加年轻VSMC中MCP-1、MMP-2和VSMC的侵袭力，直至达到未治疗的老细胞的水平。总之，MCP-1/MMP-2/TGF-β 1的这种复杂的局部信号传导回路在年龄相关的动脉内膜细胞结构和纤维化的起始和进展中起着基石作用。 中断这种恶性循环是老年人动脉健康的潜在治疗方法。

In this study, dual staining shows that MCP-1 and TGF-beta1, a powerful profibrogenic cytokine, markedly increases and co-localizes within the aortic wall in the thickened, intima of rats, nonhuman primates, and humans with aging. Cardiovascular signaling network analysis indicates that MCP-1 interacts with TGF-beta1. and is centrally located and directly connected with the inflammation cascade, which is closely associated with MMP-2 activation. In vitro study shows that MCP-1 elevates MMP2, a known activator of latent TGF-beta1 in a dose- or time-dependent manner through CCR-2 signaling in cultured VSMC from young (8 mo) rat aortae, reaching the levels of old cells (30mo). MCP-1 treatment increases activated intracellular and extracellular TGF-beta1 and its downstream molecules collagen types I and III, which is dependent upon MMP-2 activation in young VSMC, reaching levels of untreated old cells. Furthermore, cellular activated TGF-beta1nis distributed and increased in VSMC subfractions, including cytosol, the organelles and the nuclei, with aging. Interestingly, knockdown of MCP-1 via siRNA or overexpression of ectopic TIMP-2 by adenovirus transfection reduces activation of MMP-2 and TGF-beta1 and production of collagen type I and III in old VSMC. Moreover, MCP-1 treatment enhances the invasive capacity of young cells in an MMP-2 activation-dependent manner, resembling that of untreated old cells. These effects are substantially reduced by both CCR-2 and an MMP inhibitor, GM 6001. Of note, TGF-beta1 treatment increases MCP-1, MMP-2, and VSMC invasiveness in a dose-dependent manner in young VSMC, up to levels of old untreated cells. Taken together, this complex local signaling loop of MCP-1/MMP-2/TGF-beta1 plays a bedrock role in the initiation and progression of age-associated arterial intimal cellularity and fibrosis. Interruption of this vicious cycle is a potential therapeutic approach to arterial health in the elderly.