Endothelium-dependent relaxations in the aorta from K(2p)6.1 knockout mice.
Endothelium-dependent relaxations in the aorta from K(2p)6.1 knockout mice.
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K(2p)6.1 敲除小鼠主动脉内皮依赖性松弛。
DOI：
10.1152/ajpregu.00126.2013
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
BryanJr,RobertM
中科院分区：
文献类型：
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作者：
Lloyd,EricE;Pandit,LavannyaM;Crossland,RandyF;Marrelli,SeanP;BryanJr,RobertM
K2P6.1或Twik-2是一种两孔结构域钾通道，是一种重要的心血管功能调节因子，在血管平滑肌和血管内皮细胞中高表达。缺乏功能性K2P6.1(K2P6.1−/−)的小鼠(8-12wk)会患高血压，血管收缩能力增强。目前尚不清楚内皮功能K2P6.1缺失是否在K2P6.1−/−小鼠血管功能障碍中起作用。我们验证了假设：K2P6.1−/−小鼠有内皮依赖性的松弛受损。K2P6.1−/−小鼠在8-12wk(青壮年)和20-24wk(成年小鼠，P<；0.01；n=8-10)时，∼均比WT小鼠高35毫米汞柱。用苯肾上腺素(10−6M)收缩胸主动脉后，用等长肌图法评价血管内皮依赖性的舒张性。与K2P6.1+/+胎相比，青年(P<；0.001；n=5)−/−小鼠主动脉ACh依赖性最大舒张率从65±1%增加到73±1%(P<；0.01；n=6)，从45±1%增加到74±1%(P<；0.01；n=5)。然而，在年轻成年和成熟K2P6.1+/+小鼠的主动脉中，环氧合酶抑制剂10−5M吲哚美辛使ACh的最大松弛增加到敲除水平。在成熟的K2P6.1−/−小鼠中，P2Y嘌呤能激动剂三磷酸腺苷和非受体激动剂A23187也能增强松弛。K2P6.1−/−的成熟成人主动脉在硝基-L-精氨酸甲酯(L-NAME)存在下，ACh介导的收缩反应减弱，而K2P6.1−/−和K2P6.1+/+组的预收缩分别为0.97mN和7.5mN(P<；0.001；n=5)。综上所述，K2P6.1−/−高血压小鼠由于抑制了吲哚美辛敏感的收缩成分而增强了主动脉内皮依赖性的松弛。
K2P6.1or TWIK-2, a two-pore domain K channel, is an important regulator of cardiovascular function.K2P6.1is highly expressed in vascular smooth muscle and endothelium. Mice (8–12 wk) lacking functionalK2P6.1(K2P6.1−/−) are hypertensive and have enhanced vascular contractility. It is not known whether the lack of functionalK2P6.1in endothelium has a role in the vascular dysfunction inK2P6.1−/−mice. We tested the hypothesis:K2P6.1−/−mice have impaired endothelium-dependent relaxations.K2P6.1−/−mice were ∼35 mmHg more hypertensive than WT mice at both 8–12 wk (young adult) and 20–24 wk (mature mice,P< 0.01;n= 8–10). Endothelium-dependent relaxations of the thoracic aorta were evaluated by isometric myography after contraction with phenylephrine (10−6M). Maximal ACh-dependent relaxations were increased from 65 ± 1% to 73 ± 1% in the aorta from young adult (P< 0.01;n= 6) and from 45 ± 1% to 74 ± 1% in the aorta from mature (P< 0.001;n= 5)K2P6.1−/−mice compared withK2P6.1+/+littermates. However, in the aorta from young adult and matureK2P6.1+/+mice, 10−5M indomethacin, a cyclooxygenase inhibitor, increased maximal ACh relaxations to knockout levels. Enhanced relaxation was also seen with ATP, a P2Ypurinergic agonist, and A23187, a nonreceptor-based agonist in matureK2P6.1−/−mice. Mature adult aorta fromK2P6.1−/−showed an attenuated ACh-mediated contraction in the presence of nitro-l-arginine methyl ester (l-NAME) and without precontraction of 0.97 mN vs. 7.5 mN inK2P6.1−/−andK2P6.1+/+(P< 0.001;n= 5). In summary,K2P6.1−/−mice, which are hypertensive, have enhanced endothelium-dependent relaxations in the aorta due to the suppression of an indomethacin-sensitive constrictor component.