Yildiz Oguzhan
Department of Pharmacology, Gülhane Military Medical Academy, Medical School, 06018 Etlik, Ankara, Turkey.
Ann N Y Acad Sci. 2007 Apr;1100:353-60. doi: 10.1196/annals.1395.038.
Aging is one of the main risk factors for the development of atherosclerosis and, therefore, for coronary artery disease. Age-associated remodeling of the vascular wall includes luminal enlargement, intimal and medial thickening, and increased vascular stiffness. As aging occurs, smooth muscle cells (SMCs) progressively migrate from the tunica media and accumulate into the tunica intima. Aging also associates with changes of SMC proliferative and apoptotic behavior and response to growth factors, such as transforming growth factor-beta1. Aging induces a reduction in the density of the alpha-subunit of Ca(2+)-activated K(+) channels in coronary smooth muscle and increases the response to endothelial constrictor factors and K(+). Accordingly, we have recently shown that the vasodilatory effect of male sex hormone testosterone, which is mediated through large conductance Ca(2+)-activated K(+) channel opening action, decreases with age. Apart from age-associated remodeling of the vascular wall, endothelial function declines with age. This is most obvious from the attenuation of endothelium-dependent dilator responses, which is a consequence of the alteration in the expression and/or activity of the endothelial nitric oxide (NO) synthase, upregulation of the inducible NO synthase, and increased formation of reactive oxygen species. In fact, in the course of aging, there is an alteration in the equilibrium between relaxing and contracting factors released by the endothelium. Hence, there is a progressive reduction in the participation of NO and endothelium-derived hyperpolarizing factor (EDHF) associated with increased participation of oxygen-derived free radicals and cyclooxygenase-derived prostanoids. Also, the endothelin-1 and angiotensin II pathways may play a role in age-related endothelial dysfunction. Aging is also associated with a reduction in the regenerative capacity of the endothelium and endothelial senescence, which is characterized by an increased rate of endothelial cell apoptosis. Thus, aging elicits several changes in the vascular endothelium gradually altering its phenotype from an anti- to a proatherosclerotic one. In conclusion, it becomes increasingly evident that the blood vessel structural and functional disturbances, which characterize vascular aging, make a major contribution to aging-related target organ damage. The use of drugs, including antioxidant therapy, lipid-lowering drugs, and estrogens, seems to be promising.
衰老为动脉粥样硬化进而为冠心病发生的主要危险因素之一。血管壁的年龄相关性重塑包括管腔扩大、内膜和中膜增厚以及血管僵硬度增加。随着衰老的发生，平滑肌细胞（SMC）逐渐从中膜迁移并积聚到内膜。衰老还与SMC增殖、凋亡行为以及对生长因子（如转化生长因子-β1）的反应变化相关。衰老导致冠状动脉平滑肌中Ca(2+)激活K(+)通道α亚基密度降低，并增加对内皮收缩因子和K(+)的反应。因此，我们最近发现，通过大电导Ca(2+)激活K(+)通道开放作用介导的雄性激素睾酮的血管舒张作用会随着年龄增长而降低。除了血管壁的年龄相关性重塑外，内皮功能也会随年龄下降。这在内皮依赖性舒张反应减弱中最为明显，这是内皮型一氧化氮（NO）合酶表达和/或活性改变、诱导型NO合酶上调以及活性氧形成增加的结果。事实上在衰老过程中，内皮释放的舒张和收缩因子之间的平衡发生了改变。因此，与氧衍生自由基和环氧化酶衍生前列腺素参与增加相关的是，NO和内皮衍生超极化因子（EDHF）的参与逐渐减少。此外，内皮素-1和血管紧张素II途径可能在与年龄相关的内皮功能障碍中起作用。衰老还与内皮的再生能力降低和内皮衰老相关，其特征是内皮细胞凋亡率增加。因此，衰老引发血管内皮的多种变化，使其表型逐渐从抗动脉粥样硬化转变为促动脉粥样硬化。总之，越来越明显的是，表征血管衰老的血管结构和功能紊乱对与衰老相关的靶器官损伤起主要作用。使用包括抗氧化治疗、降脂药物和雌激素在内的药物似乎很有前景。
