Cellular and molecular biology of aging endothelial cells.
Cellular and molecular biology of aging endothelial cells.
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DOI：
10.1016/j.yjmcc.2015.01.021
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发表时间：
2015-12
影响因子：
5
通讯作者：
Lesniewski LA
中科院分区：
文献类型：
--
作者：
Donato AJ;Morgan RG;Walker AE;Lesniewski LA
心血管疾病(CVD)是美国主要的死亡原因，而衰老是CVD发展的主要风险因素。与年龄相关的主要动脉表型之一被认为是导致老年人心血管疾病发展的主要原因之一是内皮功能障碍。在年轻人中，内皮功能受传统的CVD危险因素的调节，但增龄与血管内皮功能障碍的发生独立相关。这种内皮功能障碍是由于内皮氧化应激和炎症下游的一氧化氮生物利用度降低所致，这可以进一步受到老年人传统心血管危险因素的调节。随着年龄的增长，更大的内皮氧化应激是由于细胞内酶NADPH氧化酶和解偶联eNOS的产生增加，以及在没有相关转录因子(如FOXO)调节的抗氧化防御适当增加的情况下来自线粒体呼吸的结果。有趣的是，NFkB是一种关键的炎性转录因子，它似乎对这种与年龄相关的内皮氧化还原变化很敏感，它的激活诱导了促炎细胞因子的转录，从而进一步抑制了内皮功能，从而形成了一个恶性循环。本文将讨论氧化应激和炎症这两个导致内皮功能障碍的宏观机制，以及导致炎症和氧化应激在老年内皮细胞中的恶性循环的细胞和分子事件。这种促炎内皮细胞表型的其他潜在介质是血管系统中免疫细胞或衰老细胞的增加。值得注意的是，基因组不稳定、端粒功能障碍或DNA损伤已被证明通过p53/p21途径触发细胞衰老，导致老年人动脉中炎症信号的增加。这篇综述将讨论关于衰老和基因组不稳定的新兴概念的知识现状，这些概念是老年内皮细胞氧化应激和炎症的潜在机制。最后，随着年龄的增长，血管内皮细胞和/或动脉中的能量敏感/应激抵抗通路(SIRT-1、AMPK、mTOR)发生改变，这些通路可能通过关键的氧化应激和炎症相关转录因子来调节内皮功能。这篇综述还将讨论“能量感应”长寿通路在调节血管内皮细胞功能中的作用。随着老年人口的增长，阐明血管内皮细胞功能障碍的细胞和分子机制对建立适当和有节制的策略至关重要，以利用旨在减轻心血管疾病风险的药物和生活方式干预。
Cardiovascular disease (CVD) is the leading cause of death in the United States and aging is a major risk factor for CVD development. One of the major age-related arterial phenotypes thought to be responsible for the development of CVD in older adults is endothelial dysfunction. Endothelial function is modulated by traditional CVD risk factors in young adults, but advancing age is independently associated with the development of vascular endothelial dysfunction. This endothelial dysfunction results from a reduction in nitric oxide bioavailability downstream of endothelial oxidative stress and inflammation that can be further modulated by traditional CVD risk factors in older adults. Greater endothelial oxidative stress with aging is a result of augmented production from the intracellular enzymes NADPH oxidase and uncoupled eNOS, as well as from mitochondrial respiration in the absence of appropriate increases in antioxidant defenses as regulated by relevant transcription factors, such as FOXO. Interestingly, it appears that NFkB, a critical inflammatory transcription factor, is sensitive to this age-related endothelial redox change and its activation induces transcription of pro-inflammatory cytokines that can further suppress endothelial function, thus creating a vicious feed-forward cycle. This review will discuss the two macro-mechanistic processes, oxidative stress and inflammation, that contribute to endothelial dysfunction with advancing age as well as the cellular and molecular events that lead to the vicious cycle of inflammation and oxidative stress in the aged endothelium. Other potential mediators of this pro-inflammatory endothelial phenotype are increases in immune or senescent cells in the vasculature. Of note, genomic instability, telomere dysfunction or DNA damage have been shown to trigger cell senescence via the p53/p21 pathway that results in increased inflammatory signaling in arteries from older adults. This review will discuss the current state of knowledge regarding the emerging concepts of senescence and genomic instability as mechanisms underlying oxidative stress and inflammation in the aged endothelium. Lastly, energy sensitive/stress resistance pathways (SIRT-1, AMPK, mTOR) are altered in endothelial cells and/or arteries with aging and these pathways may modulate endothelial function via key oxidative stress and inflammation-related transcription factors. This review will also discuss what is known about the role of “energy sensing” longevity pathways in modulating endothelial function with advancing age. With the growing population of older adults, elucidating the cellular and molecular mechanisms of endothelial dysfunction with age is critical to establishing appropriate and measured strategies to utilize pharmacological and lifestyle interventions aimed at alleviating CVD risk.