Reduced sarco/endoplasmic reticulum Ca2+ uptake activity can account for the reduced response to NO, but not sodium nitroprusside, in hypercholesterolemic rabbit aorta
Reduced sarco/endoplasmic reticulum Ca2+ uptake activity can account for the reduced response to NO, but not sodium nitroprusside, in hypercholesterolemic rabbit aorta
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DOI：
10.1161/hc3501.093798
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发表时间：
2001-08-28
期刊：
影响因子：
37.8
通讯作者：
Cohen, RA
中科院分区：
文献类型：
--
作者：
Adachi, T;Matsui, R;Cohen, RA
背景-高胆固醇血症（HC）损害乙酰胆碱诱导的舒张，但对NO供体硝普钠（SNP）引起的舒张影响不大，表明HC中乙酰胆碱从内皮释放的NO较少。然而，HC主动脉平滑肌对真实NO气体的松弛也受损，表明平滑肌反应异常。NO通过cGMP依赖性和非依赖性机制舒张动脉，并且该反应涉及通过肌质/内质网钙ATP酶（SERCA）的钙（Ca 2+）库再填充。我们研究了cGMP和SERCA参与HC兔主动脉平滑肌对NO和SNP的反应。方法和结果选择性鸟苷酸环化酶抑制剂1H-[1，2，4]-恶二唑-[4，3-a]喹喔啉-1-酮消除了正常和HC主动脉中SNP诱导的舒张，但仅部分阻断了NO诱导的舒张。残余松弛NO仍然较少HC和，在正常和HC主动脉，被取消的SERCA抑制剂环匹阿尼酸（CPA）的伴随管理。相比之下，CPA不影响SNP诱导的舒张在正常或HC主动脉。通过Ca-45（2+）摄取测量的SERCA活性在HC中显著降低，尽管SERCA 2蛋白表达没有显著改变。结论-这些数据表明NO诱导的舒张而不是SNP部分地由cGMP非依赖性的Ca 2+摄取介导到肌浆网/内质网中，并且肌浆网/内质网Ca 2+泵功能降低可以解释HC中对NO的反应受损。
Background-Hypercholesterolemia (HC) impairs acetylcholine-induced relaxation but has little effect on that caused by the NO donor sodium nitroprusside (SNP), suggesting that acetylcholine releases less NO from the endothelium in HC. The relaxation to authentic NO gas, however, is also impaired in HC aortic smooth muscle, indicating an abnormal smooth muscle response. NO relaxes arteries by both cGMP-dependent and -independent mechanisms, and the response involves calcium (Ca2+) store refilling via the, sarco/endoplasmic reticulum calcium ATPase (SERCA). We studied the involvement of cGMP and SERCA in the smooth muscle response to NO and SNP in HC rabbit aorta.Methods and Results-A selective guanylyl cyclase inhibitor, 1H-[1,2,4]-oxadiazole-[4,3-a]quinoxalin-1-one, eliminated SNP-induced relaxation but only partially blocked NO-induced relaxation in both normal and HC aorta. The residual relaxation to NO was still less in HC and, in both normal and HC aorta, was abolished by concomitant administration of the SERCA inhibitor cyclopiazonic acid (CPA). In contrast, CPA did not affect SNP-induced relaxation in either normal or HC aorta. SERCA activity measured by Ca-45(2+) uptake was markedly decreased in HC, although SERCA2 protein expression did not change significantly.Conclusions-These data suggest that NO-induced relaxation but not that to SNP is partially mediated by cGMP-independent Ca2+ uptake into sarco/endoplasmic reticulum and that reduced sarco/endoplasmic reticulum Ca2+ pump function can account for the impaired response to NO in HC.