Central Arterial Aging: Humans to Molecules

中枢动脉老化：人类到分子

• 批准号: 7327098
• 负责人: Edward G Lakatta
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7327098
• 关键词: Central; Arterial; Aging; Humans; Molecules

The structure and function of central arteries change throughout the lifetime of humans. An understanding of how the arterial wall ages is crucial not only because of its profound effects on arterial and cardiac structure and function, but also because the central artery, remodeled by aging, sets the stage for arterial diseases. It is well known that the diffuse intima thickening is a hallmark of the central arteries that accompanies advancing age, but the molecular mechanisms remain poorly understood. A series of studies on arterial aging in rodents, nonhuman primates, and humans have been performed in our group. In Fisher 344 corssbred Brown Norway rats (FXBN), the marked age-associated increases in the angiotensin II (Ang II) protein, martix metalloproteinase-2 activation (MMP-2), and transforming growth factor-B1 (TGF-B1). Are observed within the thickened arterial intima, including infiltrated vascular smooth muscle cells (VSMCs) and deposited collagen and fibronectin (FN). Interestingly, in older male monkeys, an upregulation of both Ang II and MMP-2 is detected in the thickened aortic intimae, contining numerous VSMC and collagen. Notably, we also found that both Ang II and MMP activity are upregulated in the thickened arterial intima of humans in areas remote from atherosclerotic plaques with aging. Thus, Ang II and MMP-2 accompany age-associated arterial remodeling. To analyze this relationship, we infused Ang II into young rats. An administration of Ang II to young rats increases arterial MMP-2 and TGF-B1 activity, intima infiltration by VSMCs, and collagen deposition. This reproduces nearly all of the aforementioned structural and molecular features of the arterial wall in young rats that have been observed in older rats. Furthermore, TGF-B1 activation is dependent, in part at least, by a concomitant age-associated increase in MMP-2 activity; and monocyte chemoattractant protein-1 (MCP-1), a downstream molecule of Ang signaling, is markedly increased within the older aortic wall in rats. These findings point at a central role for Ang II and associated signaling molecules in arterial aging. MMP-2, MCP-1, TGF-B1, collagen and FN production are all downstream events of Ang II-AT1 receptor signaling. The age-associated increases of these related molecules within the older remodeled aorta implicate local arterial Ang II signaling pathways as targets for prevention or amelioration of arterial remodeling, and its attendant risk for the incidence and severity of arterial diseases that increase exponentially with advancing age.

中央动脉的结构和功能在人类的整个生命中发生变化。了解动脉壁的年龄如何至关重要，这不仅是因为其对动脉和心脏结构和功能的深远影响，还因为衰老重塑的中央动脉为动脉疾病树立了阶段。众所周知，弥漫性内膜增厚是伴随年龄的中央动脉的标志，但分子机制仍然很少了解。在我们的小组中，已经对啮齿动物，非人类灵长类动物和人类进行了一系列有关动脉衰老的研究。在Fisher 344 CORSSBRED棕色挪威大鼠（FXBN）中，血管紧张素II（ANG II）蛋白，Martix金属蛋白酶2激活（MMP-2）的显着年龄相关的增加和转化生长因子-B1（TGF-B1）（TGF-B1）。在增厚的动脉内膜中观察到，包括浸润的血管平滑肌细胞（VSMC）以及沉积的胶原蛋白和纤连蛋白（FN）。有趣的是，在老年雄性猴子中，在增厚的主动脉膜中检测到了ANG II和MMP-2的上调，延续了许多VSMC和胶原蛋白。值得注意的是，我们还发现，在远离衰老的动脉粥样硬化斑块的地区，人类增厚的动脉内膜中，ANG II和MMP活性都上调。因此，ANG II和MMP-2伴随着与年龄相关的动脉重塑。为了分析这种关系，我们将Ang II注入了年轻的大鼠。 ANG II对年轻大鼠的施用会增加动脉MMP-2和TGF-B1活性，VSMCS的内膜浸润和胶原蛋白沉积。这几乎再现了在老鼠中观察到的年轻大鼠中动脉壁的上述结构和分子特征。此外，TGF-B1激活至少部分取决于与年龄相关的MMP-2活性的增加。单核细胞化学吸引蛋白1（MCP-1）是ANG信号的下游分子，在大鼠较旧的主动脉壁内显着增加。 这些发现指出了ANG II的中心作用以及动脉衰老中相关的信号分子。 MMP-2，MCP-1，TGF-B1，胶原蛋白和FN的产生都是ANG II-AT1受体信号传导的下游事件。这些相关分子在较旧的主动脉中与年龄相关的增加，这意味着局部动脉ANG II信号通路是预防或改善动脉重塑的靶标，并且其随附的动脉疾病发生率和严重性的风险随着增长的年龄而增加。