Tyrosine phosphorylation of Kv1.5 is upregulated in intrauterine growth retardation rats with exaggerated pulmonary hypertension.
Tyrosine phosphorylation of Kv1.5 is upregulated in intrauterine growth retardation rats with exaggerated pulmonary hypertension.
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Kv1.5 酪氨酸磷酸化在患有过度肺动脉高压的宫内生长迟缓大鼠中上调
DOI：
10.1590/1414-431x20176237
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发表时间：
2017-09-12
期刊：
影响因子：
--
通讯作者：
Du LZ
中科院分区：
文献类型：
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作者：
Fu LC;Lv Y;Zhong Y;He Q;Liu X;Du LZ
胎儿宫内发育迟缓(IUGR)与成人发病相关，包括肺动脉高压。然而，早期营养不良导致晚年肺血管功能障碍的潜在机制尚不完全清楚。在这里，我们研究了电压门控钾通道1.5(Kv1.5)的酪氨酸磷酸化在这一导致成人血管功能障碍加重的产前事件中的作用。采用IUGR后慢性低氧大鼠模型(12周龄低氧2周)，通过测定雄性大鼠的肺动脉收缩压和血管内径，探讨宫内营养不良对大鼠肺动脉的生理和结构影响。检测Kv1.5蛋白表达和酪氨酸磷酸化水平。结果发现，14周龄大鼠缺氧2周后，IUGR使平均肺动脉压升高，肺血管平滑肌层增厚，而常氧组无明显变化。在IUGR低氧大鼠的PASMCs中，Kv1.5基因和蛋白的表达显著降低，而酪氨酸磷酸化的Kv1.5基因的表达显著增加。这些结果表明，IUGR导致慢性缺氧性肺动脉高压(CH-PAH)的加重，并伴随着PASMCs Kv1.5表达的降低。这一现象可能与PASMCs中Kv1.5蛋白酪氨酸磷酸化水平升高有关，为IUGR相关性CH-PAH的防治提供了新的思路。
Intrauterine growth retardation (IUGR) is associated with the development of adult-onset diseases, including pulmonary hypertension. However, the underlying mechanism of the early nutritional insult that results in pulmonary vascular dysfunction later in life is not fully understood. Here, we investigated the role of tyrosine phosphorylation of voltage-gated potassium channel 1.5 (Kv1.5) in this prenatal event that results in exaggerated adult vascular dysfunction. A rat model of chronic hypoxia (2 weeks of hypoxia at 12 weeks old) following IUGR was used to investigate the physiological and structural effect of intrauterine malnutrition on the pulmonary artery by evaluating pulmonary artery systolic pressure and vascular diameter in male rats. Kv1.5 expression and tyrosine phosphorylation in pulmonary artery smooth muscle cells (PASMCs) were determined. We found that IUGR increased mean pulmonary artery pressure and resulted in thicker pulmonary artery smooth muscle layer in 14-week-old rats after 2 weeks of hypoxia, while no difference was observed in normoxia groups. In the PASMCs of IUGR-hypoxia rats, Kv1.5 mRNA and protein expression decreased while that of tyrosine-phosphorylated Kv1.5 significantly increased. These results demonstrate that IUGR leads to exaggerated chronic hypoxia pulmonary arterial hypertension (CH-PAH) in association with decreased Kv1.5 expression in PASMCs. This phenomenon may be mediated by increased tyrosine phosphorylation of Kv1.5 in PASMCs and it provides new insight into the prevention and treatment of IUGR-related CH-PAH.