Sexually dimorphic mechanisms of H2O2-mediated dilation in porcine coronary arterioles with ischemia and endurance exercise training.

IF 3.3 3区 医学 Q1 PHYSIOLOGY
Journal of applied physiology Pub Date : 2025-04-01 Epub Date: 2025-03-10 DOI:10.1152/japplphysiol.00761.2024
Kalen Johnson, Jeff F Bray, Cristine L Heaps
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Abstract

We determined the impact of sex on H2O2-mediated dilation in coronary arterioles and the contribution of K+ channels after exercise training in ischemic heart disease. We hypothesized that arterioles from male and female swine would similarly display impaired H2O2-induced dilation after chronic occlusion that would be corrected by exercise training. Yucatan miniswine were surgically instrumented with an ameroid constrictor around the proximal left circumflex artery, gradually inducing occlusion and a collateral-dependent myocardium. Arterioles from the left anterior descending artery myocardial region served as nonoccluded controls. Eight weeks postoperatively, swine of each sex were separated into sedentary and exercise-trained (progressive treadmill regimen; 5 days/wk for 14 wk) groups. Collateral-dependent arterioles of sedentary female pigs displayed impaired sensitivity to H2O2 that was reversed with exercise training. In contrast, male pigs exhibited enhanced sensitivity to H2O2 in collateral-dependent versus nonoccluded arterioles in both sedentary and exercise-trained groups. Large-conductance, calcium-dependent K+ (BKCa) and 4-aminopyridine (AP)-sensitive voltage-gated K+ (Kv) channels contributed to H2O2-mediated dilation in nonoccluded and collateral-dependent arterioles of exercise-trained females, but not in arterioles of sedentary female or sedentary or exercise-trained male swine. BKCa channel, protein kinase A (PKA), and protein kinase G (PKG) protein levels were not significantly different between groups, nor were kinase enzymatic activities. Taken together, our studies suggest that in female swine, exercise training stimulates the coupling of H2O2 signaling with BKCa and 4-AP-sensitive Kv channels, compensating for impaired dilation in collateral-dependent arterioles. Interestingly, coronary arterioles from neither sedentary female or male swine, regardless of training status, depended upon BKCa or 4-AP-sensitive Kv channels for H2O2-mediated dilation.NEW & NOTEWORTHY The current studies reveal sexually dimorphic adaptations to H2O2-mediated dilation, and unique contributions of K+ channels, in coronary arterioles from swine subjected to chronic ischemia and exercise training; findings important for development of therapeutic strategies. In female swine, chronic ischemia attenuates dilation, which is reversed by exercise training via BKCa and Kv channel stimulation. In male swine, ischemia enhances dilation to H2O2, which is further augmented by exercise training and independent of BKCa and Kv channels.

h2o2介导的猪冠状动脉缺血和耐力运动训练扩张的两性二态机制。
我们确定了性别对缺血性心脏病运动训练后h2o2介导的冠状动脉扩张的影响以及K+通道的贡献。我们假设雄性和雌性猪的小动脉在慢性闭塞后同样会表现出h2o2诱导的扩张受损,这可以通过运动训练来纠正。Yucatan miniwine在左旋动脉近端周围置入Ameroid缩窄器,逐渐诱导闭塞和侧支依赖性心肌。左前降支心肌区域的小动脉作为未闭塞的对照。术后8周,每种性别的猪被分为久坐和运动训练(渐进式跑步机方案;5天/周,共14周)组。久坐不动的母猪侧支依赖性小动脉对H2O2的敏感性受损,运动训练逆转了这一现象。相比之下,在久坐组和运动训练组中,雄性猪在侧枝依赖的小动脉中对H2O2的敏感性高于未闭塞的小动脉。大电导、钙依赖性K+ (BKCa)和4-氨基吡啶敏感电压门控K+ (Kv)通道有助于运动训练的雌性非闭塞和侧支依赖性小动脉的h2o2介导的扩张,但在久坐的雌性或久坐或运动训练的雄性猪的小动脉中没有。各组间BKCa通道、PKA和PKG蛋白水平无显著差异,激酶酶活性也无显著差异。综上所述,我们的研究表明,在雌性猪中,运动训练刺激H2O2信号与BKCa和4- ap敏感的Kv通道的耦合,补偿了侧支依赖性小动脉扩张受损。有趣的是,无论训练状态如何,久坐的母猪或公猪的冠状动脉都依赖于BKCa或4- ap敏感的Kv通道进行h2o2介导的扩张。
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来源期刊
CiteScore
6.00
自引率
9.10%
发文量
296
审稿时长
2-4 weeks
期刊介绍: The Journal of Applied Physiology publishes the highest quality original research and reviews that examine novel adaptive and integrative physiological mechanisms in humans and animals that advance the field. The journal encourages the submission of manuscripts that examine the acute and adaptive responses of various organs, tissues, cells and/or molecular pathways to environmental, physiological and/or pathophysiological stressors. As an applied physiology journal, topics of interest are not limited to a particular organ system. The journal, therefore, considers a wide array of integrative and translational research topics examining the mechanisms involved in disease processes and mitigation strategies, as well as the promotion of health and well-being throughout the lifespan. Priority is given to manuscripts that provide mechanistic insight deemed to exert an impact on the field.
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