Nakano Masayuki, Koga Motokazu, Hashimoto Tatsuo, Matsushita Natsuki, Masukawa Daiki, Mizuno Yusuke, Uchimura Hiraku, Niikura Ryo, Miyazaki Tomoyuki, Nakamura Fumio, Zou Suo, Shimizu Takahiro, Saito Motoaki, Tamura Kouichi, Goto Takahisa, Goshima Yoshio
Department of Molecular Pharmacology and Neurobiology, Graduate School of Medicine, Yokohama City University, Yokohama, 236-0004, Japan; Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, 236-0004, Japan.
Department of Molecular Pharmacology and Neurobiology, Graduate School of Medicine, Yokohama City University, Yokohama, 236-0004, Japan; Department of Anesthesiology, Graduate School of Medicine, Yokohama City University, Yokohama, 236-0004, Japan; Department of Anesthesiology, Kanagawa Cancer Center, Yokohama, 241-8515, Japan.
J Pharmacol Sci. 2022 Feb;148(2):214-220. doi: 10.1016/j.jphs.2021.11.008. Epub 2021 Dec 2.
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 generated Gpr143 gene-deficient (Gpr143) rats, and confirmed that DOPA did not augment phenylephrine-induced contractile response in Gpr143 rat pulmonary arteries. We utilized a rat model of monocrotaline (MCT)-induced PH. In the MCT model, the right ventricular systolic pressure was attenuated in the Gpr143 rats than in WT rats. Phenylephrine-induced cell migration and proliferation were also suppressed in Gpr143 pulmonary 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.
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、右心室肥厚，最终引发右心衰竭。然而，其潜在的病理生理机制仍知之甚少。我们之前发现，3,4-左旋二羟基苯丙氨酸（DOPA）通过肾上腺素能受体α1（ADRA1）与G蛋白偶联受体143（GPR143，一种DOPA受体）之间的偶联，使血管运动反应对交感神经张力敏感。我们研究了DOPA是否同样增强从大鼠分离的肺动脉中ADRA1介导的收缩，以及GPR143是否参与PH的发病机制。用1μM DOPA预处理分离的肺动脉可增强对ADRA1激动剂去氧肾上腺素的血管收缩反应，但对血栓素A2激动剂U-46619或内皮素-1无此作用。我们培育了Gpr143基因缺陷（Gpr143）大鼠，并证实DOPA不会增强Gpr143大鼠肺动脉中去氧肾上腺素诱导的收缩反应。我们利用了野百合碱（MCT）诱导的PH大鼠模型。在MCT模型中，Gpr143大鼠的右心室收缩压比野生型（WT）大鼠降低。与WT细胞相比，Gpr143肺动脉平滑肌细胞中去氧肾上腺素诱导的细胞迁移和增殖也受到抑制。我们的结果表明，GPR143参与了PH大鼠模型的发病机制。
