Right ventricular overloading is attenuated in monocrotaline-induced pulmonary hypertension model rats with a disrupted Gpr143 gene, the gene that encodes the 3,4-l-dihydroxyphenyalanine (l-DOPA) receptor.
Right ventricular overloading is attenuated in monocrotaline-induced pulmonary hypertension model rats with a disrupted Gpr143 gene, the gene that encodes the 3,4-l-dihydroxyphenyalanine (l-DOPA) receptor.
复制标题
在野百合碱诱导的肺动脉高压模型大鼠中，Gpr143 基因（编码 3,4-l-二羟基苯丙氨酸 (l-DOPA) 受体的基因）受到破坏，右心室超负荷会减弱。
DOI：
10.1016/j.jphs.2021.11.008
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Goshima Y.
中科院分区：
文献类型：
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作者：
Nakano M;Koga M;Hashimoto T;Matsushita N;Masukawa D;Mizuno Y;Uchimura H;Niikura R;Miyazaki T;Nakamura F;Zou S;Shimizu T;Saito M;Tamura K;Goto T;Goshima Y.
肺动脉高压（PH）是一种严重的进行性疾病，可导致右心室收缩压升高、右心室肥大并最终导致右心衰竭。然而，其潜在的病理生理机制知之甚少。我们先前表明，3，4-l-二羟基苯丙氨酸（DOPA）通过肾上腺素能受体α 1（ADRA 1）和G蛋白偶联受体143（GPR 143）（DOPA受体）之间的偶联使血管对交感神经张力的反应增敏。我们研究了多巴是否同样增强了大鼠肺动脉中ADRA 1介导的收缩，以及GPR 143是否参与了PH的发病机制。用DOPA 1 μM预处理离体肺动脉可增强对苯肾上腺素（一种ADRA 1激动剂）的血管收缩反应，但对U-46619（一种血栓烷A2激动剂或内皮素-1）无反应。我们制备了Gpr 143基因缺陷（Gpr 143-/y）大鼠，证实多巴不增强苯肾上腺素诱导的Gpr 143-/y大鼠肺动脉收缩反应。我们利用野百合碱（MCT）诱导的大鼠PH模型。在MCT模型中，Gpr 143-/y大鼠的右心室收缩压比WT大鼠降低。苯肾上腺素诱导的细胞迁移和增殖也抑制Gpr 143-/pulgaris动脉平滑肌细胞比野生型细胞。我们的研究结果表明，GPR 143参与了PH大鼠模型的PH发病机制。
Pulmonary hypertension (PH) is a severe and progressive disease that causes elevated right ventricular systolic pressure, right ventricular hypertrophy and ultimately right heart failure. However, the underlying pathophysiologic mechanisms are poorly understood. We previously showed that 3,4-l-dihydroxylphenyalanine (DOPA) sensitizes vasomotor response to sympathetic tone via coupling between the adrenergic receptor alpha1 (ADRA1) and a G protein-coupled receptor 143 (GPR143), a DOPA receptor. We investigated whether DOPA similarly enhances ADRA1-mediated contraction in pulmonary arteries isolated from rats, and whether GPR143 is involved in the PH pathogenesis. Pretreating the isolated pulmonary arteries with DOPA 1 μM enhanced vasoconstriction in response to phenylephrine, an ADRA1 agonist, but not to U-46619, a thromboxane A2 agonist or endothelin-1. We generatedGpr143gene-deficient (Gpr143-/y) rats, and confirmed that DOPA did not augment phenylephrine-induced contractile response inGpr143-/yrat pulmonary arteries. We utilized a rat model of monocrotaline (MCT)-induced PH. In the MCT model, the right ventricular systolic pressure was attenuated in theGpr143-/yrats than in WT rats. Phenylephrine-induced cell migration and proliferation were also suppressed inGpr143-/ypulmonary artery smooth muscle cells than in WT cells. Our result suggests that GPR143 is involved in the PH pathogenesis in the rat models of PH.