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オクニシ カツヒデ
Okunishi Katsuhide
奥西 勝秀 所属 東邦大学 医学部 医学科 職種 教授 |
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| 論文種別 | 原著 |
| 言語種別 | 英語 |
| 査読の有無 | 査読あり |
| 表題 | Distinct PKA regulatory subunits mediate PGE2 inhibition of TGFβ-1-stimulated collagen I translation and myofibroblast differentiation. |
| 掲載誌名 | 正式名：American journal of physiology. Lung cellular and molecular physiology ISSNコード：1040-0605/1522-1504 |
| 掲載区分 | 国外 |
| 出版社 | AMER PHYSIOLOGICAL SOC |
| 巻・号・頁 | 313(4),pp.L722-L731-L731 |
| 著者・共著者 | Scott H Wettlaufer,L Raghu Penke,Katsuhide Okunishi,Marc Peters-Golden |
| 発行年月 | 2017/10/01 |
| 概要 | Prostaglandin E2 (PGE2), via cAMP signaling, inhibits a variety of fibroblast functions relevant to fibrogenesis. Among these are their translation of collagen I protein and their differentiation to myofibroblasts. PKA is central to these actions, with cAMP binding to regulatory (R) subunits leading to the release of catalytic subunits. Here we examined the role of specific PKAR subunit isoforms in these inhibitory actions in transforming growth factor β-1 (TGFβ-1)-stimulated human lung fibroblasts (HLFs). HLFs expressed all four R subunit isoforms. siRNA-mediated knockdown of subunits PKARIα and PKARIIα had no effect on PGE2 inhibition of either process. However, knockdown of PKARIβ selectively attenuated PGE2 inhibition of collagen I protein expression, whereas knockdown of PKARIIβ selectively attenuated PGE2 inhibition of expression of the myofibroblast differentiation marker, α-smooth muscle actin (α-SMA). cAMP analogs that selectively activate either PKARIβ or PKARIIβ exclusively inhibited collagen I synthesis or differentiation, respectively. In parallel, the PKARIβ agonist (but not a PKARIIβ agonist) reduced phosphorylation of two proteins involved in protein translation, protein kinase B (AKT) and mammalian target of rapamycin (mTOR). By contrast, the PKARIIβ agonist (but not a PKARIβ agonist) reduced levels of the differentiation-associated phosphorylated focal adhesion kinase (p-FAK) as well as the relative mRNA and protein expression of serum response factor (SRF), a transcription factor necessary for myofibroblast differentiation. Our results demonstrate that cAMP inhibition of collagen I translation and myofibroblast differentiation reflects the actions of distinct PKAR subunits. |
| DOI | 10.1152/ajplung.00131.2017 |
| PMID | 28729346 |