NF-κB-Dependent Upregulation of NCX1 Induced by Angiotensin II Contributes to Calcium Influx in Rat Aortic Smooth Muscle Cells

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• 作者：Bei Liu ; PhD^a ; Lixia Yang ; PhD^c ; Bin Zhang ; MD^b ; Chenwei Kuang ; MD^c ; Shiliang Huang ; MD^c ; Ruiwei Guo ; MD ; PhD^c ; ^{grw771210@163.com" class="auth_mail" title="E-mail the corresponding author}
• 刊名：Canadian Journal of Cardiology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：32
• 期：11
• 页码：1356.e11-1356.e20
• 全文大小：2337 K

文摘

The reverse mode of Na⁺/Ca²⁺ exchanger (NCX) 1 can transport Ca²⁺ into cells and is involved in the contractile regulation of vascular smooth muscle cells (VSMCs) and the development of hypertension. We hypothesized that upregulation of NCX1 expression induced by angiotensin II (Ang II) could be dependent on activation of nuclear factor–kappa B (NF-κB) and contributes to Ca²⁺ influx in VSMCs.

Methods

An osmotic minipump was implanted for administration of Ang II in Sprague-Dawley rats, and blood pressure, as well as NCX1 expression, in the aorta was measured. VSMCs were cultured to verify that Ang II–upregulated NCX1 expression is dependent on activation of NF-κB and contributes to Ca²⁺ influx.

Results

Ang II–upregulated NCX1 expression in rat aortas (2.1-fold at day 6) and VSMCs (1.7-fold at 24 hours) and NF-κB knockdown and p38 mitogen-activated protein kinase (MAPK) inhibitor resulted in 2.1- and 2.0-fold decreases in Ang II–upregulated NCX1 expression in VSMCs. KB-R7943 (an inhibitor of NCX1 reversal) and NCX1 knockdown decreased Ang II–induced Ca²⁺ influx 1.4- and 1.3- fold, respectively. KB-R7943 and removal of extracellular Na⁺ decreased Ang II–initiated store depletion–mediated Ca²⁺ entry by 1.5- and 1.3-fold, respectively. Moreover, NF-κB knockdown and use of a p38 MAPK inhibitor resulted in about 1.3-fold decreases in Ang II–induced Ca²⁺ influx through activation of reverse-mode NCX1.

Conclusions

Ang II upregulates NCX1 expression through p38 MAPK and NF-κB pathways, and reverse-mode NCX1 plays an important part in Ang II-induced Ca²⁺ influx in VSMCs, which may be associated with Ang II–initiated store-operated channel entry.