Comparison of endothelial function, O2−· and H2O2 production, and vascular oxidative stress resistance between the longest-living rodent, the naked mole rat, and mice

Abstract

Vascular aging is characterized by decreased nitric oxide (NO) bioavailability, oxidative stress, and enhanced apoptotic cell death. We hypothesized that interspecies comparative assesment 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 ∼ 16 yr) and guinea pigs (GPs, Cavia porcellus; ML ∼ 6 yr) have intermediate longevity, whereas laboratory mice are short living (ML ∼ 3.5 yr). We compared interspecies differences in endothelial function, O₂⁻· and H₂O₂ 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 O₂⁻· (lucigenin chemiluminescence and ethidium bromide fluorescence) and H₂O₂ (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, H₂O₂ (from 10⁻⁶ to 10⁻³ mol/l) and heat exposure (42°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 H₂O₂ enhanced apoptotic cell death, whereas heat exposure did not increase DNA fragmentation rate. Interspecies comparison showed there is a negative correlation between H₂O₂-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.