Calcium-mediated signaling and calmodulin-dependent kinase regulate hepatocyte-inducible nitric oxide synthase expression.
Calcium-mediated signaling and calmodulin-dependent kinase regulate hepatocyte-inducible nitric oxide synthase expression.
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DOI：
10.1016/j.jss.2014.07.042
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发表时间：
2015-02
影响因子：
2.2
通讯作者：
Harbrecht, Brian G.
中科院分区：
文献类型：
--
作者：
Zhang, Baochun;Crankshaw, Will;Nesemeier, Ryan;Patel, Jay;Nweze, Ikenna;Lakshmanan, Jaganathan;Harbrecht, Brian G.
一氧化氮合酶（iNOS）在肝细胞中由休克和炎症刺激诱导。诱导型一氧化氮合酶产生的过量一氧化氮介导休克诱导的肝损伤和死亡，因此了解诱导型一氧化氮合酶的调节将有助于阐明感染性休克的病理生理机制。在体外，细胞因子通过激活包括丝裂原活化蛋白激酶和核因子κB的信号通路诱导iNOS表达。细胞因子还诱导钙（Ca2+）动员并激活钙介导的细胞内信号传导途径，通常通过激活钙调蛋白依赖性激酶（CaMK）。钙调节巨噬细胞中NO的产生，但钙和钙介导的信号传导在肝细胞iNOS表达中的作用尚未确定。原代大鼠肝细胞分离，培养，并诱导产生NO与促炎细胞因子。钙动员和Ca2+介导的信号转导改变与离子载体，Ca2+通道阻滞剂，和抑制剂的CaMK。Ca2+离子载体A23187抑制了精氨酸刺激的NO产生，而EGTA和硝苯地平增加了NO产生、iNOS mRNA和iNOS蛋白表达。用KN 93和CBD抑制CaMK增加NO的产生，但钙调磷酸酶抑制剂FK 506降低iNOS的表达。这些数据表明，钙介导的信号调节肝细胞iNOS的表达，并通过一个独立的钙调神经磷酸酶的机制。细胞内钙离子水平的变化可能调节促炎细胞因子诱导的肝脏炎症过程中iNOS的表达。
Nitric oxide synthase (iNOS) is induced in hepatocytes by shock and inflammatory stimuli. Excessive NO from iNOS mediates shock-induced hepatic injury and death so understanding the regulation of iNOS will help elucidate the pathophysiology of septic shock. In vitro, cytokines induce iNOS expression through activation of signaling pathways including mitogen-activated protein kinases and Nuclear Factor κB. Cytokines also induce calcium (Ca2+) mobilization and activate calcium-mediated intracellular signaling pathways, typically through activation of calmodulin-dependent kinases (CaMK). Calcium regulates NO production in macrophages but the role of calcium and calcium-mediated signaling in hepatocyte iNOS expression has not been defined. Primary rat hepatocytes were isolated, cultured, and induced to produce NO with proinflammatory cytokines. Calcium mobilization and Ca2+-mediated signaling were altered with ionophore, Ca2+ channel blockers, and inhibitors of CaMK. The Ca2+ ionophore A23187 suppressed cytokine-stimulated NO production while EGTA and nifedipine increased NO production, iNOS mRNA, and iNOS protein expression. Inhibition of CaMK with KN93 and CBD increased NO production but the calcineurin inhibitor FK 506 decreased iNOS expression. These data demonstrate that calcium-mediated signaling regulates hepatocyte iNOS expression and does so through a mechanism independent of calcineurin. Changes in intracellular calcium levels may regulate iNOS expression during hepatic inflammation induced by pro-inflammatory cytokines.
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DOI：
10.1073/pnas.131200398
发表时间：
2001-08-28
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
3.8
作者：
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通讯作者：
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影响因子：
3.1
作者：
Menezes, JM;Hierholzer, C;Harbrecht, BG
通讯作者：
Harbrecht, BG
DOI：
10.1152/ajpheart.00932.2001
发表时间：
2003-06-01
影响因子：
4.8
作者：
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通讯作者：
Dinh-Xuan, AT
DOI：
10.1152/ajpgi.1999.277.1.g144
发表时间：
1999-07-01
影响因子：
4.5
作者：
Menezes, J;Hierholzer, C;Harbrecht, BG
通讯作者：
Harbrecht, BG