Dedifferentiation of Human Cardiac Myofibroblasts Is Independent of Activation of COX-2/PGE2 Pathway

Abstract

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 E2 (PGE2) has been shown to dedifferentiate human lung myofibroblasts. The role of activation of the COX-2/PGE2 pathway in dedifferentiation of cardiac myofibroblasts remains unknown. Here, we show that phorbol 12-myristate 13-acetate (PMA) but not PGE2 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 PGE2 in human cardiac myofibroblasts. Pretreatment of myofibroblasts with NS-398, a selective COX-2 inhibitor, and PF-04418948, a selective PGE2 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 PGE2 has no effects on dedifferentiation of cardiac myofibroblasts. PMA-induced dedifferentiation of cardiac myofibroblast is independent of activation of COX-2 and PGE2 pathway. The mechanism in PMA-induced reversal of cardiac myofibroblasts needs to be explored further.

A Comprehensive Overview of Organ Inflammatory Responses: Genesis, Possible Mechanisms, and Mediators of Inflammation

“…Angiotensin II induces MAPK in cardiac fibroblasts, resulting in myocardial hypertrophy, and upregulates COX-2. 133 Angiotensin II also enhanced IL-6 and TNF-synthesis in the heart and kidneys, according to in vivo studies. Proinflammatory cytokine release is maintained by increased endothelin 1 expression and decreased natriuretic peptide levels, which are connected to increased NO synthesis by iNOS and decreased myocardial contractility.…”