From the Department of Chemistry, University of Cambridge, United Kingdom (M.D.).
British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, King's College London, United Kingdom (A.M.C., C.M.S.).
Arterioscler Thromb Vasc Biol. 2020 Jul;40(7):e193-e202. doi: 10.1161/ATVBAHA.120.313792. Epub 2020 May 14.
Vascular calcification is a ubiquitous pathology of aging. Oxidative stress, persistent DNA damage, and senescence are major pathways driving both cellular and tissue aging, and emerging evidence suggests that these pathways are activated, and even accelerated, in patients with vascular calcification. The DNA damage response-a complex signaling platform that maintains genomic integrity-is induced by oxidative stress and is intimately involved in regulating cell death and osteogenic differentiation in both bone and the vasculature. Unexpectedly, a posttranslational modification, PAR (poly[ADP-ribose]), which is a byproduct of the DNA damage response, initiates biomineralization by acting to concentrate calcium into spheroidal structures that can nucleate apatitic mineral on the ECM (extracellular matrix). As we start to dissect the molecular mechanisms driving aging-associated vascular calcification, novel treatment strategies to promote healthy aging and delay pathological change are being unmasked. Drugs targeting the DNA damage response and senolytics may provide new avenues to tackle this detrimental and intractable pathology.
血管钙化是衰老的一种普遍病理现象。氧化应激、持续的 DNA 损伤和衰老，是驱动细胞和组织衰老的主要途径，而新出现的证据表明，这些途径在患有血管钙化的患者中被激活，甚至加速。DNA 损伤反应——一个维持基因组完整性的复杂信号平台——是由氧化应激诱导的，并在骨骼和血管中调节细胞死亡和成骨分化方面发挥着重要作用。出乎意料的是，一种翻译后修饰，即 PAR（多聚[ADP-核糖]），它是 DNA 损伤反应的副产物，通过将钙浓缩成球状结构来启动生物矿化，这些结构可以在 ECM（细胞外基质）上成核磷灰石矿。随着我们开始剖析与衰老相关的血管钙化的分子机制，促进健康衰老和延缓病理性变化的新治疗策略正在被揭示。针对 DNA 损伤反应和衰老细胞的药物可能为解决这种有害且棘手的病理提供新途径。
