TRPC channel-derived calcium fluxes differentially regulate ATP and flow-induced activation of eNOS.
TRPC channel-derived calcium fluxes differentially regulate ATP and flow-induced activation of eNOS.
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TRPC通道衍生的钙流量差异调节ATP和流量诱导的eNOS激活。
DOI：
10.1016/j.niox.2021.03.005
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发表时间：
2021-06-01
期刊：
影响因子：
--
通讯作者：
Barbee KA
中科院分区：
文献类型：
--
作者：
Muzorewa TT;Buerk DG;Jaron D;Barbee KA
内皮功能障碍，以一氧化氮(NO)生物利用度受损为特征，是对各种心血管危险因素的反应，是动脉粥样硬化的先兆。NO是通过严格调节内皮型一氧化氮合酶(ENOS)活性而产生的，以响应血管扩张刺激。这种内皮型一氧化氮合酶的调节在一定程度上是通过钙离子内流(SOCE)实现的。我们假设，ATP和Flow诱导的eNOS激活都受到来自Orai1通道和瞬时受体潜在规范(TRPC)通道家族成员的SOCE的调节。用药物拮抗剂TRPC通道和Orai1对牛主动脉内皮细胞(BAECs)进行预处理，观察其对钙信号转导和eNOS激活的影响。我们发现，抑制TRPC3可以减弱ATP诱导的峰值和持续的钙信号以及由此产生的eNOS激活。阻断TRPC4可降低ATP刺激后的瞬时钙离子浓度峰值，但不能显著降低eNOS活性。同时抑制TRPC3和4通过改变磷酸化介导的eNOS活性来减少流动诱导的NO产生。抑制TRPC1/6或Orai1不能降低ATP诱导的钙内流或eNOS的激活。我们的结果表明，TRPC3在BAECs中是一种存储操作的通道，是ATP诱导的eNOS激活的关键调节因子，而流动刺激也招募TRPC4进入合成NO的途径。
Endothelial dysfunction, characterised by impaired nitric oxide (NO) bioavailability, arises in response to a variety of cardiovascular risk factors and precedes atherosclerosis. NO is produced by tight regulation of endothelial nitric oxide synthase (eNOS) activity in response to vasodilatory stimuli. This regulation of eNOS is mediated in part by store-operated calcium entry (SOCE). We hypothesised that both ATP- and flow-induced eNOS activation are regulated by SOCE derived from Orai1 channels and members of the transient receptor potential canonical (TRPC) channel family. Bovine aortic endothelial cells (BAECs) were pre-treated with pharmacological inhibitors of TRPC channels and Orai1 to examine their effect on calcium signaling and eNOS activation in response to flow and ATP. The peak and sustained ATP-induced calcium signal and the resulting eNOS activation were attenuated by inhibition of TRPC3, which we found to be store operated. TRPC4 blockade reduced the transient peak in calcium concentration following ATP stimulation, but did not significantly reduce eNOS activity. Simultaneous TRPC3 & 4 inhibition reduced flow-induced NO production via alterations in phosphorylation-mediated eNOS activity. Inhibition of TRPC1/6 or Orai1 failed to lower ATP-induced calcium entry or eNOS activation. Our results suggest that TRPC3 is a store-operated channel in BAECs and is the key regulator of ATP-induced eNOS activation, whereas flow stimulation also recruits TRPC4 into the pathway for the synthesis of NO.
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胆固醇富集会损害电容性钙进入，eNOS磷酸化和剪切应力引起的无产生。
影响因子：
2.8
作者：
Andrews AM;Muzorewa TT;Zaccheo KA;Buerk DG;Jaron D;Barbee KA
通讯作者：
Barbee KA
DOI：
10.1016/j.niox.2010.08.003
发表时间：
2010-12-15
期刊：
Nitric oxide : biology and chemistry
影响因子：
--
作者：
Andrews AM;Jaron D;Buerk DG;Kirby PL;Barbee KA
通讯作者：
Barbee KA
影响因子：
4.5
作者：
Fleming, Ingrid
通讯作者：
Fleming, Ingrid
影响因子：
3.7
作者：
Just S;Chenard BL;Ceci A;Strassmaier T;Chong JA;Blair NT;Gallaschun RJ;Del Camino D;Cantin S;D'Amours M;Eickmeier C;Fanger CM;Hecker C;Hessler DP;Hengerer B;Kroker KS;Malekiani S;Mihalek R;McLaughlin J;Rast G;Witek J;Sauer A;Pryce CR;Moran MM
通讯作者：
Moran MM
影响因子：
5.5
作者：
Jagnandan, D;Sessa, WC;Fulton, D
通讯作者：
Fulton, D