The protective effects of PCPA against monocrotaline-induced pulmonary arterial hypertension are mediated through the downregulation of NFAT-1 and NF-κB.
The protective effects of PCPA against monocrotaline-induced pulmonary arterial hypertension are mediated through the downregulation of NFAT-1 and NF-κB.
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PCPA 对野百合碱诱导的肺动脉高压的保护作用是通过下调 NFAT-1 和 NF-B 介导的
DOI：
10.3892/ijmm.2017.3001
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发表时间：
2017-07
影响因子：
5.4
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Bai Y;Li ZX;Wang HL;Lian GC;Wang Y
炎症和重构在肺动脉高压（PAH）的发病机制中起作用。核因子-κB（NF-κB）和活化T细胞核因子-1（NFAT-1）参与许多疾病的炎症和重塑。4-氯-DL-苯丙氨酸（PCPA）作为色氨酸羟化酶抑制剂，具有抗炎和重塑作用。因此，我们推测PCPA可能通过NFAT-1和NF-κB信号通路减轻野百合碱（MCT）诱导的PAH。为了证实我们的假设，我们将68只Sprague-Dawley雄性大鼠分为4组：对照组、MCT组、MCT + P1组和MCT + P2组。MCT以60 mg/kg的剂量通过腹膜内注射给药一次。PCPA以50或100 mg/kg的剂量通过腹膜内注射给药，每天一次，连续21天。测定血流动力学指标，并对肺组织进行形态学分析。Western blot和免疫组化检测NF-κB B p-65和NFAT-1的表达。Western blot检测磷酸化NF-κB激酶抑制剂（p-IKK）、IKK、磷酸化细胞外信号调节激酶（p-ERK）、ERK、细胞间粘附分子1（ICAM-1）和白细胞介素6（IL-6）的表达水平。发现MCT可显著诱导PAH，伴肺组织炎症和重塑。这与NFAT-1、p-IKK、p-ERK和核p65的表达增加有关。PCPA可显著减轻MCT诱导的炎症反应和动脉重塑，降低NFAT-1及NF-κB信号通路相关蛋白的表达。上述结果表明，PCPA抑制MCT诱导的炎症和动脉重塑的作用与下调PAH大鼠的NFAT-1和NF-κB信号通路有关。
Inflammation and remodeling play a role in the pathogenesis of pulmonary arterial hypertension (PAH). Nuclear factor-κB (NF-κB) and nuclear factor of activated T cells-1 (NFAT-1) participate in inflammation and remodeling in a number of diseases. As a tryptophan hydroxylase inhibitor, 4-chloro-DL-phenylalanine (PCPA) had been reported to exert anti-inflammatory and remodeling effects. Therefore, we hypothesized that PCPA may attenuate monocrotaline (MCT)-induced PAH through the NFAT-1 and NF-κB signaling pathways. In order to confirm our hypothesis, we divided 68 Sprague-Dawley male rats into 4 groups as follows: the control, MCT, MCT + P1 and MCT + P2 groups. MCT was administered at a dose of 60 mg/kg once via intraperitoneal injection. PCPA was administered via intraperitoneal injection at a dose of 50 or 100 mg/kg once daily for 21 consecutive days. We then measured the hemodynamic index and morphological analysis was carried out on the lung tissues. Western blot analysis and immunohistochemistry were used to examine the levels of NFAT-1 and NF-κB p-65. The expression levels of phosphorylated inhibitor of NF-κB kinase (p-IKK), IKK, phosphorylated extracellular signal-regulated kinase (p-ERK), ERK, intercellular adhesion molecule-1 (ICAM-1) and interleukin-6 (IL-6) were examined by western blot analysis. MCT was found to significantly induce PAH, with inflammation and remodeling of the lung tissues. This was associatd with an increased expression of NFAT-1, p-IKK, p-ERK and nuclear p65. PCPA significantly attenuated MCT-induced inflammation and arterial remodeling, and decreased the expression of NFAT-1, as well as that of relevant proteins of the NF-κB signaling pathway. The above-mentioned findings suggest that the inhibitory effects of PCPA on MCT-induced inflammation and arterial remodeling are related to the downregulation of the NFAT-1 and NF-κB signaling pathways in rats with PAH.