Department of Kinesiology, University of Connecticut, Storrs, CT, USA.
Department of Surgery, Huntsman Cancer Hospital, University of Utah, Salt Lake City, UT, USA.
J Physiol. 2019 Apr;597(7):1791-1804. doi: 10.1113/JP277410. Epub 2019 Feb 27.
The present study aimed to determine the impact of ageing on endogenous adropin levels in human skeletal muscle feed arteries (SMFAs) and the role of adropin in age-related vascular dysfunction. Adropin protein expression falls progressively with advancing age in the human peripheral vasculature. Endothelial-dependent vasodilatation, typically attenuated with age, was strongly correlated with SMFA adropin protein levels. Adropin incubation restored age-related endothelial-dependent vasodilatory dysfunction and increased the phosphorylated endothelial nitric oxide synthase (eNOS)/eNOS ratio in an age-dependent manner in the SMFAs. The role of nitric oxide bioavailability was additionally indicated by NOS blockade ablating both the positive vascular effects of adropin incubation and the relationship between endothelial function and adropin protein expression. Additional evidence of a mechanistic link between declining adropin and age-related endothelial dysfunction was documented by a progressively increasing magnitude of effect of adropin-induced eNOS-mediated vasodilatation with ageing. Adropin appears to be a novel therapeutic target for facilitating the restoration of endothelial function with ageing.
The present study aimed to determine the impact of advancing age on endogenous adropin levels in human skeletal muscle feed arteries (SMFAs) and the role of adropin in age-related vascular dysfunction. Adropin protein expression and vasodilatory capacity was assesed in SMFAs from Young (27 ± 2 years, n = 10), Middle Aged (54 ± 2 years, n = 10) and Old (75 ± 2 years, n = 16) subjects. Endothelial-dependent vasodilatation, with and without adropin incubation, was assessed in response to flow-induced shear stress and ACh. Both SMFA adropin protein expression and endothelial-dependent vasodilatory function exhibited a progressive, age-related, reduction (Flow: Y: 65 ± 3%; Middle Aged: 36 ± 3%; Old: 15 ± 2%; ACh: Young: 63 ± 2%, Middle Aged: 34 ± 3%; Old: 23 ± 3%, P < 0.05). There was a strong positive correlation between SMFA adropin protein expression and both flow (r = 0.81, P < 0.05) and ACh (r = 0.78, P < 0.05). Adropin incubation in the Middle Aged and Old SMFAs restored the vasodilatory response to flow (Middle Aged + Adropin: 59 ± 3%; Old + Adropin: 47 ± 3%, P < 0.05) and ACh (Middle Aged + Adropin: 59 ± 3%; Old + Adropin: 49 ± 2%, P < 0.05). A mechanistic link between adropin and nitric oxide (NO) biovavailabilty was supported by (i) increased phosphorylated endothelial NO synthase (eNOS)/eNOS protein expression with adropin incubation only in the Middle Aged and Old SMFAs; (ii) eNOS blockade ablating both the positive vascular effects of adropin incubation and the relationship between endothelial function and adropin protein expression and (iii) a progressive increase in the magnitude of effect of adropin-induced eNOS-mediated vasodilatation with advancing age. Adropin could be a novel therapeutic target for facilitating the restoration of endothelial function via increased NO bioavailability, with advancing age.
本研究旨在确定衰老对人骨骼肌营养动脉（SMFAs）内源性阿屈进水平的影响，以及阿屈进在与年龄相关的血管功能障碍中的作用。阿屈进蛋白表达随年龄增长在人体外周血管中呈渐进性下降。内皮依赖性血管舒张作用通常随年龄增长而减弱，与 SMFA 阿屈进蛋白水平呈强烈相关性。阿屈进孵育以年龄依赖的方式恢复了与年龄相关的内皮依赖性血管舒张功能障碍，并增加了 SMFAs 中磷酸化内皮型一氧化氮合酶（eNOS）/eNOS 比值。一氧化氮生物利用度的作用还通过一氧化氮合酶阻断消除阿屈进孵育的阳性血管作用以及内皮功能与阿屈进蛋白表达之间的关系来证明。随着年龄的增长，阿屈进诱导的 eNOS 介导的血管舒张作用的效应幅度逐渐增大，这为阿屈进与与年龄相关的内皮功能障碍之间的机制联系提供了额外的证据。阿屈进似乎是一种促进内皮功能恢复的新的治疗靶点。
本研究旨在确定衰老对人骨骼肌营养动脉（SMFAs）内源性阿屈进水平的影响，以及阿屈进在与年龄相关的血管功能障碍中的作用。在年轻（27 ± 2 岁，n = 10）、中年（54 ± 2 岁，n = 10）和老年（75 ± 2 岁，n = 16）受试者的 SMFAs 中评估了阿屈进蛋白表达和血管舒张能力。在存在和不存在阿屈进孵育的情况下，通过血流诱导的切应力和乙酰胆碱评估内皮依赖性血管舒张作用。SMFA 阿屈进蛋白表达和内皮依赖性血管舒张功能均呈进行性、年龄相关的降低（血流：Y：65 ± 3%；中年：36 ± 3%；老年：15 ± 2%；乙酰胆碱：年轻：63 ± 2%，中年：34 ± 3%；老年：23 ± 3%，P < 0.05）。SMFA 阿屈进蛋白表达与血流（r = 0.81，P < 0.05）和乙酰胆碱（r = 0.78，P < 0.05）呈强烈正相关。在中年和老年 SMFAs 中孵育阿屈进恢复了对血流（中年+阿屈进：59 ± 3%；老年+阿屈进：47 ± 3%，P < 0.05）和乙酰胆碱（中年+阿屈进：59 ± 3%；老年+阿屈进：49 ± 2%，P < 0.05）的血管舒张反应。阿屈进与一氧化氮（NO）生物利用度之间的机制联系得到支持（i）仅在中年和老年 SMFAs 中，阿屈进孵育增加了磷酸化内皮型一氧化氮合酶（eNOS）/eNOS 蛋白表达；（ii）eNOS 阻断消除了阿屈进孵育的阳性血管作用以及内皮功能与阿屈进蛋白表达之间的关系；（iii）随着年龄的增长，阿屈进诱导的 eNOS 介导的血管舒张作用的效应幅度呈进行性增大。阿屈进可能是一种新的治疗靶点，可通过增加一氧化氮生物利用度促进内皮功能恢复，随着年龄的增长。
