Disruption of sarcolemmal ATP-sensitive potassium channel activity impairs the cardiac response to systolic overload.
Disruption of sarcolemmal ATP-sensitive potassium channel activity impairs the cardiac response to systolic overload.
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DOI：
10.1161/circresaha.107.170795
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发表时间：
2008-10-24
影响因子：
20.1
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Hu X;Xu X;Huang Y;Fassett J;Flagg TP;Zhang Y;Nichols CG;Bache RJ;Chen Y
肌膜ATP敏感性钾通道(KATP)作为代谢感受器，促进左心室(LV)对能量需求变化的适应。这项研究利用心脏特异性KATP活性中断的转基因小鼠品系(SUR1-TG小鼠)或Kir6.2基因缺失(Kir6.2 KO)，研究了KATP功能障碍损害左室应激反应的机制。在非应激条件下，SUR1-TG和Kir6.2KO小鼠均具有正常的左心室质量和功能。与相应的野生型对照相比，SUR1-TG和Kir6.2KO小鼠在慢性横断性主动脉缩窄(TAC)后均表现出更严重的左心室肥厚和功能障碍。SUR1-TG和Kir6.2KO小鼠均能显著降低PGC-1α̣和一组能量代谢相关基因在蛋白质和̃水平的表达。此外，阻断KATP抑制了培养的乳鼠心肌细胞对低氧的反应，抑制了PGC-1α的表达和启动子活性，表明KATP活性是维持应激条件下PGC-1α表达所必需的。前列环素α基因缺失也加重了他汀类药物所致的慢性心肌肥厚和功能障碍，提示前列环素α缺失可加重收缩超负荷所致的心功能不全。SUR1-TG和Kir6.2KO小鼠在TAC后FOXO_1均降低，这与FOXO_1降低可抑制PGC-1α表达的报道一致。此外，抑制KATP导致与pGC-1α启动子相关的FOXO_1表达减少。这些数据表明，KATP通道通过调节PGC-1α及其靶基因来促进心脏对应激的反应，至少部分是通过FOXO1途径。
Sarcolemmal ATP sensitive potassium Channels (KATP) act as metabolic sensors that facilitate adaptation of the left ventricle (LV) to changes in energy requirements. This study examined the mechanism by which KATP dysfunction impairs the LV response to stress using transgenic mouse strains with cardiac specific disruption of KATP activity (SUR1-tg mice) or Kir6.2 gene deficiency (Kir6.2 KO). Both SUR1-tg and Kir6.2 KO mice had normal LV mass and function under unstressed conditions. Following chronic transverse aortic constriction (TAC), both SUR1-tg and Kir6.2 KO mice developed more severe LV hypertrophy and dysfunction as compared with their corresponding wild type controls. Both SUR1-tg and Kir6.2 KO mice had significantly decreased expression of PGC-1α̣ and a group of energy metabolism related genes at both protein and mRNA levels̃. Furthermore, disruption of KATP repressed expression and promoter activity of PGC-1α in cultured rat neonatal cardiac myocytes in response to hypoxia, indicating that KATP activity is required to maintain PGC-1α expression under stress conditions. PGC1α gene deficiency also exacerbated chronic TAC-induced ventricular hypertrophy and dysfunction, suggesting that depletion of PGC1α can worsen systolic overload induced ventricular dysfunction. Both SUR1-tg and Kir6.2 KO mice had decreased FOXO1 after TAC, in agreement with the reports that a decrease of FOXO1 can repress PGC-1α expression. Furthermore, inhibition of KATP caused a decrease of FOXO1 associated with PGC-1α promoter. These data indicate that KATP channels facilitate the cardiac response to stress by regulating PGC-1α and its target genes, at least partially through the FOXO1 pathway.