Streese Lukas, Khan Abdul Waheed, Deiseroth Arne, Hussain Shafaat, Suades Rosa, Tiaden Andre, Kyburz Diego, Cosentino Francesco, Hanssen Henner
Department of Sport, Exercise and Health, Medical Faculty, University of Basel, Birsstrasse 320 B, 4052 Basel, Switzerland.
Cardiology Unit, Department of Medicine Solna, Karolinska Institute, Karolinska Universitetssjukhuset, Solna S1:02 171 76 Stockholm, Sweden.
Eur Heart J. 2020 Apr 14;41(15):1514-1519. doi: 10.1093/eurheartj/ehz196.
Impairments of retinal vessel diameter are associated with major adverse cardiovascular (CV) events. Promoter DNA methylation is a repressor of the mitochondrial adaptor p66Shc gene transcription, a key driver of ageing-induced reactive oxygen species. The study aimed to investigate whether high-intensity interval training (HIIT) affects retinal microvascular phenotype as well as p66Shc expression and oxidative stress in ageing subjects with increased CV risk from the EXAMIN AGE cohort.
Eighty-four sedentary subjects (mean age 59.4 ± 7.0 years) with ≥2 CV risk factors were randomized into either a 12-week HIIT or standard physical activity recommendations. Retinal arteriolar and venular diameters were measured by use of a retinal vessel analyser. As a marker of oxidative stress plasma 3-nitrotyrosine (3-NT) level was determined by ELISA. Gene expression of p66Shc and DNA methylation were assessed in mononuclear cells by RT-qPCR and methylated-DNA capture (MethylMiner Enrichment Kit) coupled with qPCR, respectively. High-intensity interval training reduced body mass index, fat mass, low-density lipoprotein and increased muscle mass, as well as maximal oxygen uptake (VO2max). Moreover, HIIT restored microvascular phenotype by inducing retinal arteriolar widening (pre: 175 ± 14 µm vs. post: 181 ± 13 µm, P = 0.001) and venular narrowing (pre: 222 ± 14 µm vs. post: 220 ± 14 µm, P = 0.007). After HIIT, restoration of p66Shc promoter methylation (P = 0.034) reduced p66Shc gene expression (P = 0.037) and, in turn, blunted 3-NT plasma levels (P = 0.002).
High-intensity interval training rescues microvascular dysfunction in ageing subjects at increased CV risk. Exercise-induced reprogramming of DNA methylation of p66Shc gene may represent a putative mechanistic link whereby exercise protects against age-related oxidative stress.
ClinicalTrials.gov: NCT02796976 (https://clinicaltrials.gov/ct2/show/NCT02796976).
视网膜血管直径受损与主要不良心血管（CV）事件相关。启动子DNA甲基化是线粒体衔接蛋白p66Shc基因转录的抑制因子，而p66Shc基因是衰老诱导的活性氧的关键驱动因子。本研究旨在调查高强度间歇训练（HIIT）是否会影响来自EXAMIN AGE队列中CV风险增加的老年受试者的视网膜微血管表型以及p66Shc表达和氧化应激。
84名久坐不动的受试者（平均年龄59.4±7.0岁），具有≥2个CV危险因素，被随机分为12周的HIIT组或标准体育活动建议组。使用视网膜血管分析仪测量视网膜小动脉和小静脉直径。通过ELISA测定作为氧化应激标志物的血浆3-硝基酪氨酸（3-NT）水平。分别通过RT-qPCR和与qPCR联用的甲基化DNA捕获（MethylMiner富集试剂盒）评估单核细胞中p66Shc的基因表达和DNA甲基化。高强度间歇训练降低了体重指数、脂肪量、低密度脂蛋白，并增加了肌肉量以及最大摄氧量（VO2max）。此外，HIIT通过诱导视网膜小动脉增宽（训练前：175±14μm vs.训练后：181±13μm，P = 0.001）和小静脉变窄（训练前：222±14μm vs.训练后：220±14μm，P = 0.007）恢复了微血管表型。HIIT后，p66Shc启动子甲基化的恢复（P = 0.034）降低了p66Shc基因表达（P = 0.037），进而降低了血浆3-NT水平（P = 0.002）。
高强度间歇训练可改善CV风险增加的老年受试者的微血管功能障碍。运动诱导的p66Shc基因DNA甲基化重编程可能代表一种假定的机制联系，通过该机制运动可预防与年龄相关的氧化应激。
ClinicalTrials.gov：NCT02796976（https://clinicaltrials.gov/ct2/show/NCT02796976）
