Labinskyy Nazar, Csiszar Anna, Orosz Zsuzsanna, Smith Kira, Rivera Aracelie, Buffenstein Rochelle, Ungvari Zoltan
Dept. of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H2698-704. doi: 10.1152/ajpheart.00534.2006.
Vascular aging is characterized by decreased nitric oxide (NO) bioavailability, oxidative stress, and enhanced apoptotic cell death. We hypothesized that interspecies comparative assessment of vascular function among rodents with disparate longevity may offer insight into the mechanisms determining successful vascular aging. We focused on four rodents that show approximately an order of magnitude range in maximum longevity (ML). The naked mole rat (NMR; Heterocephalus glaber) is the longest-living rodent known (ML > 28 yr), Damara mole rats (DMRs, Cryptomys damarensis; ML approximately 16 yr) and guinea pigs (GPs, Cavia porcellus; ML approximately 6 yr) have intermediate longevity, whereas laboratory mice are short living (ML approximately 3.5 yr). We compared interspecies differences in endothelial function, O(2)(-)* and H(2)O(2) production, and resistance to apoptotic stimuli in blood vessels. Sensitivity to acetylcholine-induced, NO-mediated relaxation was smaller in carotid arteries from NMRs, GPs, and DMRs than in mouse vessels. Measurements of production of O(2)(-)* (lucigenin chemiluminescence and ethidium bromide fluorescence) and H(2)O(2) (dichlorofluorescein fluorescence) showed that free radical production in vascular endothelial and smooth muscle cells is comparable in vessels of the three longer-living species and in arteries of shorter-living mice. In mouse arteries, H(2)O(2) (from 10(-6) to 10(-3) mol/l) and heat exposure (42 degrees C for 15-45 min) enhanced apoptotic cell death, as indicated by an increased DNA fragmentation rate and increased caspase 3/7 activity. In NMR vessels, only the highest doses of H(2)O(2) enhanced apoptotic cell death, whereas heat exposure did not increase DNA fragmentation rate. Interspecies comparison showed there is a negative correlation between H(2)O(2)-induced apoptotic cell death and ML. Thus endothelial vasodilator function and vascular production of reactive oxygen species do not correlate with maximal lifespan, whereas increased lifespan potential is associated with an increased vascular resistance to proapoptotic stimuli.
血管衰老的特征是一氧化氮（NO）生物利用度降低、氧化应激以及凋亡性细胞死亡增加。我们推测，对寿命不同的啮齿动物的血管功能进行种间比较评估，可能有助于深入了解决定血管成功衰老的机制。我们重点研究了四种最大寿命（ML）相差约一个数量级的啮齿动物。裸鼹鼠（NMR；裸鼹形鼠）是已知最长寿的啮齿动物（ML>28岁），达马拉鼹鼠（DMR，南非囊鼠；ML约16岁）和豚鼠（GP，豚鼠；ML约6岁）寿命中等，而实验室小鼠寿命较短（ML约3.5岁）。我们比较了种间在内皮功能、超氧阴离子（O₂⁻）和过氧化氢（H₂O₂）生成以及血管对凋亡刺激的抗性方面的差异。与小鼠血管相比，NMR、GP和DMR颈动脉对乙酰胆碱诱导的、NO介导的舒张反应敏感性较低。对超氧阴离子（O₂⁻）生成（光泽精化学发光和溴化乙锭荧光法）和过氧化氢（H₂O₂）生成（二氯荧光素荧光法）测量显示，在三种长寿物种的血管以及短寿小鼠的动脉中，血管内皮和平滑肌细胞中的自由基生成相当。在小鼠动脉中，过氧化氢（浓度从10⁻⁶到10⁻³mol/L）和热暴露（42℃，15 - 45分钟）会增加凋亡性细胞死亡，表现为DNA片段化率增加和半胱天冬酶3/7活性增加。在NMR血管中，只有最高剂量的过氧化氢会增加凋亡性细胞死亡，而热暴露并未增加DNA片段化率。种间比较显示，过氧化氢诱导的凋亡性细胞死亡与最大寿命之间呈负相关。因此，内皮舒张功能和血管活性氧生成与最大寿命无关，而寿命潜力增加与血管对促凋亡刺激的抗性增加有关。
