Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Xi'an Medical University, Xi'an, Shaanxi, China.
Department of Pharmacology, Xi'an Medical University, Xi'an, Shaanxi, China.
Environ Toxicol. 2019 Oct;34(10):1094-1104. doi: 10.1002/tox.22810. Epub 2019 Jun 14.
Fine particulate matter (PM ) is an important environmental risk factor for cardiovascular diseases. However, little is known about the effects of PM on arteries. The present study investigated whether PM alters 5-hydroxytryptamine (5-HT) receptor expression and inflammatory mediators on rat mesenteric arteries, and examined the underlying mechanisms. Isolated rat mesenteric arteries segments were cultured with PM in the presence or absence of ERK1/2, JNK, and p38 pathway inhibitors. Contractile reactivity was monitored by a sensitive myograph. The expression of 5-HT receptors and inflammatory mediators were studied by a real-time polymerase chain reaction and/or by immunohistochemistry. The phosphorylation of mitogen-activated protein kinases (MAPK) pathway was detected by Western blot. Compared with the fresh or culture alone groups, 1.0 μg/mL PM cultured for 16 hours significantly enhanced contractile response induced by 5-HT and increased 5-HT receptor mRNA and protein expressions, indicating PM upregulates 5-HT receptor. SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor) significantly decreased PM -induced elevated contraction and mRNA and protein expression of 5-HT receptor. Cultured with PM significantly increased the mRNA expression of inflammatory mediators (NOS2, IL-1β, and TNF-α), while SB203580 decreased mRNA expression level of NOS2, IL-1β, and TNF-α. SP600125 (JNK inhibitor) decreased mRNA expression level of TNF-α and IL-1β. After PM exposure, the phosphorylation of p38 and ERK1/2 protein were increased. SB203580 and U0126 inhibited the PM caused increased phosphorylation protein of p38 and ERK1/2. In conclusion, PM induces inflammatory-mediated MAPK pathway in artery which subsequently results in enhanced vascular contraction responding to 5-HT via the upregulated 5-HT receptors.
细颗粒物 (PM) 是心血管疾病的一个重要环境风险因素。然而，人们对 PM 对动脉的影响知之甚少。本研究探讨了 PM 是否会改变大鼠肠系膜动脉中 5-羟色胺 (5-HT) 受体的表达和炎症介质，并研究了其潜在机制。将分离的大鼠肠系膜动脉段与 PM 一起培养，存在或不存在 ERK1/2、JNK 和 p38 通路抑制剂。通过敏感的肌动描记器监测收缩反应性。通过实时聚合酶链反应和/或免疫组织化学研究 5-HT 受体和炎症介质的表达。通过 Western blot 检测丝裂原激活蛋白激酶 (MAPK) 途径的磷酸化。与新鲜或单独培养组相比，1.0μg/mL PM 培养 16 小时后，5-HT 诱导的收缩反应显著增强，并增加 5-HT 受体 mRNA 和蛋白表达，表明 PM 上调 5-HT 受体。SB203580(p38 抑制剂)和 U0126(ERK1/2 抑制剂)显著降低了 PM 诱导的收缩增强和 5-HT 受体的 mRNA 和蛋白表达。与 PM 共培养显著增加了炎症介质 (NOS2、IL-1β 和 TNF-α) 的 mRNA 表达，而 SB203580 降低了 NOS2、IL-1β 和 TNF-α 的 mRNA 表达水平。SP600125(JNK 抑制剂)降低了 TNF-α 和 IL-1β 的 mRNA 表达水平。暴露于 PM 后，p38 和 ERK1/2 蛋白的磷酸化增加。SB203580 和 U0126 抑制了 PM 引起的 p38 和 ERK1/2 磷酸化蛋白的增加。总之，PM 诱导动脉中的炎症介导的 MAPK 途径，随后通过上调的 5-HT 受体增强对 5-HT 的血管收缩反应。
