Dedifferentiation of Human Cardiac Myofibroblasts Is Independent of Activation of COX-2/PGE<sub>2</sub> Pathway
The differentiation of cardiac fibroblasts to myofibroblasts is considered to be a critical step in activation and progression of cardiac fibrosis in heart disease. TGF-β is one of the key cytokines that promotes transition of fibroblasts to myofibroblasts. Dedifferentiation of formed myofibroblasts...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/6/3023 |
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| author | Vy Tran Luu Sang Phan Zhu-Qiu Jin |
| author_facet | Vy Tran Luu Sang Phan Zhu-Qiu Jin |
| author_sort | Vy Tran Luu |
| collection | DOAJ |
| description | The differentiation of cardiac fibroblasts to myofibroblasts is considered to be a critical step in activation and progression of cardiac fibrosis in heart disease. TGF-β is one of the key cytokines that promotes transition of fibroblasts to myofibroblasts. Dedifferentiation of formed myofibroblasts or reversal of formed myofibroblasts to fibroblasts remains incompletely understood. Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) has been shown to dedifferentiate human lung myofibroblasts. The role of activation of the COX-2/PGE<sub>2</sub> pathway in dedifferentiation of cardiac myofibroblasts remains unknown. Here, we show that phorbol 12-myristate 13-acetate (PMA) but not PGE<sub>2</sub> induces dedifferentiation of de novo adult human cardiac myofibroblasts stimulated by TGF-β1 from human cardiac fibroblasts as evidenced by reduced expression of α-smooth muscle actin (α-SMA). PMA remarkably increased endogenous levels of PGE<sub>2</sub> in human cardiac myofibroblasts. Pretreatment of myofibroblasts with NS-398, a selective COX-2 inhibitor, and PF-04418948, a selective PGE<sub>2</sub> receptor type 2 (EP2) antagonist, had no effect on expression of α-SMA nor abolished the dedifferentiation induced by PMA. Our results indicated that endogenous and exogenous PGE<sub>2</sub> has no effects on dedifferentiation of cardiac myofibroblasts. PMA-induced dedifferentiation of cardiac myofibroblast is independent of activation of COX-2 and PGE<sub>2</sub> pathway. The mechanism in PMA-induced reversal of cardiac myofibroblasts needs to be explored further. |
| first_indexed | 2024-03-09T19:43:09Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T19:43:09Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2e0c6c9b7c724e21801cb9c4bc8c75c92023-11-24T01:30:46ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01236302310.3390/ijms23063023Dedifferentiation of Human Cardiac Myofibroblasts Is Independent of Activation of COX-2/PGE<sub>2</sub> PathwayVy Tran Luu0Sang Phan1Zhu-Qiu Jin2Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA 95757, USADepartment of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA 95757, USADepartment of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA 95757, USAThe differentiation of cardiac fibroblasts to myofibroblasts is considered to be a critical step in activation and progression of cardiac fibrosis in heart disease. TGF-β is one of the key cytokines that promotes transition of fibroblasts to myofibroblasts. Dedifferentiation of formed myofibroblasts or reversal of formed myofibroblasts to fibroblasts remains incompletely understood. Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) has been shown to dedifferentiate human lung myofibroblasts. The role of activation of the COX-2/PGE<sub>2</sub> pathway in dedifferentiation of cardiac myofibroblasts remains unknown. Here, we show that phorbol 12-myristate 13-acetate (PMA) but not PGE<sub>2</sub> induces dedifferentiation of de novo adult human cardiac myofibroblasts stimulated by TGF-β1 from human cardiac fibroblasts as evidenced by reduced expression of α-smooth muscle actin (α-SMA). PMA remarkably increased endogenous levels of PGE<sub>2</sub> in human cardiac myofibroblasts. Pretreatment of myofibroblasts with NS-398, a selective COX-2 inhibitor, and PF-04418948, a selective PGE<sub>2</sub> receptor type 2 (EP2) antagonist, had no effect on expression of α-SMA nor abolished the dedifferentiation induced by PMA. Our results indicated that endogenous and exogenous PGE<sub>2</sub> has no effects on dedifferentiation of cardiac myofibroblasts. PMA-induced dedifferentiation of cardiac myofibroblast is independent of activation of COX-2 and PGE<sub>2</sub> pathway. The mechanism in PMA-induced reversal of cardiac myofibroblasts needs to be explored further.https://www.mdpi.com/1422-0067/23/6/3023COX-2dedifferentiationmyofibroblastPGE<sub>2</sub>Phorbol 12-myristate 13-acetate |
| spellingShingle | Vy Tran Luu Sang Phan Zhu-Qiu Jin Dedifferentiation of Human Cardiac Myofibroblasts Is Independent of Activation of COX-2/PGE<sub>2</sub> Pathway International Journal of Molecular Sciences COX-2 dedifferentiation myofibroblast PGE<sub>2</sub> Phorbol 12-myristate 13-acetate |
| title | Dedifferentiation of Human Cardiac Myofibroblasts Is Independent of Activation of COX-2/PGE<sub>2</sub> Pathway |
| title_full | Dedifferentiation of Human Cardiac Myofibroblasts Is Independent of Activation of COX-2/PGE<sub>2</sub> Pathway |
| title_fullStr | Dedifferentiation of Human Cardiac Myofibroblasts Is Independent of Activation of COX-2/PGE<sub>2</sub> Pathway |
| title_full_unstemmed | Dedifferentiation of Human Cardiac Myofibroblasts Is Independent of Activation of COX-2/PGE<sub>2</sub> Pathway |
| title_short | Dedifferentiation of Human Cardiac Myofibroblasts Is Independent of Activation of COX-2/PGE<sub>2</sub> Pathway |
| title_sort | dedifferentiation of human cardiac myofibroblasts is independent of activation of cox 2 pge sub 2 sub pathway |
| topic | COX-2 dedifferentiation myofibroblast PGE<sub>2</sub> Phorbol 12-myristate 13-acetate |
| url | https://www.mdpi.com/1422-0067/23/6/3023 |
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