Mitochondria control functional CaV1.2 expression in smooth muscle cells of cerebral arteries.
Mitochondria control functional CaV1.2 expression in smooth muscle cells of cerebral arteries.
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DOI：
10.1161/circresaha.110.224345
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发表时间：
2010-09-03
影响因子：
20.1
通讯作者：
Jaggar JH
中科院分区：
文献类型：
--
作者：
Narayanan D;Xi Q;Pfeffer LM;Jaggar JH
线粒体在收缩性动脉肌细胞中的生理功能知之甚少。线粒体可以摄取钙（Ca 2+），但调节线粒体Ca 2+浓度（[Ca 2 +] mito）的细胞内Ca 2+信号及其变化的生理功能尚不清楚。识别调节[Ca 2 +]mito的Ca 2+信号，检查[Ca 2 +]mito变化的意义，并检验[Ca 2 +]mito控制阻力大小脑动脉肌细胞中功能性离子通道转录的假设。内皮素-1（ET-1）通过激活三磷酸肌醇受体（IP 3R）激活钙波，升高心肌细胞内钙浓度（[Ca 2 +]i）。IP 3R介导的肌浆网（SR）Ca 2+释放增加[Ca 2 +]mito并诱导线粒体去极化，这刺激线粒体活性氧（mitoROS）产生，从而升高胞质ROS。相反，整体[Ca 2 +]i升高并不改变[Ca 2 +]mito、线粒体电位或mitoROS生成。ET-1刺激核因子κ B（NF-κB）p50亚单位核转位，ET-1诱导IP 3 R介导的mitoROS升高NF-κ B依赖的转录活性。ET-1升高电压依赖性Ca 2+（CaV1.2）通道表达，导致压力（肌源性张力）和去极化诱导的血管收缩增加。IP 3R抑制、线粒体电子传递链阻断、抗氧化剂处理和NF-κB亚基敲低均降低了CaV1.2表达的基线水平和ET-1诱导的CaV1.2表达的升高，导致血管舒张。IP 3R介导的SR Ca 2+释放升高[Ca 2 +]mito，其诱导mitoROS产生。MitoROS激活NF-κB，其刺激CaV 1.2通道转录。因此，线粒体感知IP 3R介导的SR Ca 2+释放，以控制动脉肌细胞中NF-κ B依赖性CaV1.2通道的表达，从而调节动脉收缩性。
Physiological functions of mitochondria in contractile arterial myocytes are poorly understood. Mitochondria can uptake calcium (Ca2+), but intracellular Ca2+ signals that regulate mitochondrial Ca2+ concentration ([Ca2+]mito) and physiological functions of changes in [Ca2+]mito in arterial myocytes are unclear. Identify Ca2+ signals that regulate [Ca2+]mito, examine the significance of changes in [Ca2+]mito, and test the hypothesis that [Ca2+]mito controls functional ion channel transcription in myocytes of resistance-size cerebral arteries. Endothelin-1 (ET-1) activated Ca2+ waves and elevated global Ca2+ concentration ([Ca2+]i) via inositol 1,4,5-trisphosphate receptor (IP3R) activation. IP3R-mediated sarcoplasmic reticulum (SR) Ca2+ release increased [Ca2+]mito and induced mitochondrial depolarization, which stimulated mitochondrial reactive oxygen species (mitoROS) generation that elevated cytosolic ROS. In contrast, a global [Ca2+]i elevation did not alter [Ca2+]mito, mitochondrial potential, or mitoROS generation. ET-1 stimulated nuclear translocation of nuclear factor kappa B (NF-κB) p50 subunit and ET-1-induced IP3R-mediated mitoROS elevated NF-κB-dependent transcriptional activity. ET-1 elevated voltage-dependent Ca2+ (CaV1.2) channel expression, leading to an increase in both pressure (myogenic tone)- and depolarization-induced vasoconstriction. Baseline CaV1.2 expression and the ET-1-induced elevation in CaV1.2 expression were both reduced by IP3R inhibition, mitochondrial electron transport chain block, antioxidant treatment, and NF-κB subunit knockdown, leading to vasodilation. IP3R-mediated SR Ca2+ release elevates [Ca2+]mito, which induces mitoROS generation. MitoROS activate NF-κB, which stimulates CaV1.2 channel transcription. Thus, mitochondria sense IP3R-mediated SR Ca2+ release to control NF-κB-dependent CaV1.2 channel expression in arterial myocytes, thereby modulating arterial contractility.