Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA 95757, USA.
Int J Mol Sci. 2022 Mar 11;23(6):3023. doi: 10.3390/ijms23063023.
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 (PGE) has been shown to dedifferentiate human lung myofibroblasts. The role of activation of the COX-2/PGE pathway in dedifferentiation of cardiac myofibroblasts remains unknown. Here, we show that phorbol 12-myristate 13-acetate (PMA) but not PGE 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 in human cardiac myofibroblasts. Pretreatment of myofibroblasts with NS-398, a selective COX-2 inhibitor, and PF-04418948, a selective PGE 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 has no effects on dedifferentiation of cardiac myofibroblasts. PMA-induced dedifferentiation of cardiac myofibroblast is independent of activation of COX-2 and PGE pathway. The mechanism in PMA-induced reversal of cardiac myofibroblasts needs to be explored further.
心肌成纤维细胞向肌成纤维细胞的分化被认为是心脏病中心脏纤维化激活和进展的关键步骤。TGF-β是促进成纤维细胞向肌成纤维细胞转化的关键细胞因子之一。已形成的肌成纤维细胞的去分化或逆转形成的肌成纤维细胞为成纤维细胞仍不完全清楚。前列腺素 E (PGE) 已被证明可使人类肺肌成纤维细胞去分化。COX-2/PGE 途径的激活在心肌成纤维细胞去分化中的作用尚不清楚。在这里，我们表明，佛波醇 12-肉豆蔻酸 13-乙酸酯 (PMA) 而非 PGE 诱导由 TGF-β1 刺激的新成人人心肌成纤维细胞从人心肌成纤维细胞中去分化，表现为α-平滑肌肌动蛋白 (α-SMA) 的表达减少。PMA 显著增加了人心肌成纤维细胞中内源性 PGE 的水平。用选择性 COX-2 抑制剂 NS-398 和选择性 PGE 受体 2 (EP2) 拮抗剂 PF-04418948 预处理肌成纤维细胞对 α-SMA 的表达没有影响，也不能消除 PMA 诱导的去分化。我们的结果表明，内源性和外源性 PGE 对心肌成纤维细胞的去分化没有影响。PMA 诱导的心肌成纤维细胞去分化不依赖于 COX-2 和 PGE 途径的激活。PMA 诱导的心肌成纤维细胞逆转的机制需要进一步探索。
