Objective To explore the mechanism by which dihydroartemisinin (DHA) regulates cardiac fibroblasts to improve myocardial repair through the Yes associated protein 1 (YAP1) - Tafazzin (TAZ) signaling axis.

Methods H9C2 cells were treated with angiotensin Ⅱ (Ang Ⅱ) for 72 hours, and then treated with DHA of different concentrations (0, 5, 10, 20, 40 nmol/L) for 72 hours. The H9C2 cells were divided into the blank control group (Con), Ang Ⅱ group, Ang Ⅱ + DHA group and Ang Ⅱ + DHA + GA-017 group. The cell viability was determined by the CCK-8 method, and the fibrosis and Hippo signaling pathology-related proteins were measured by Western blotting. Twenty-four male C57/BL6 mice were randomly divided into 4 groups: the control group, Ang Ⅱ group, Ang Ⅱ + DHA groupand Ang Ⅱ + DHA + GA-017 group, with 6 mice in each group. Fourteen days later, Sirius red (PSR) staining was performed to determine the collagen expression level in the left ventricle.

Results Compared with the Con group, the viability of H9C2 cells in the Ang Ⅱ + DHA (0 nmol/L) group was significantly reduced (P ＜ 0.05), while the viability of H9C2 cells in the Ang Ⅱ + DHA (20 nmol/L) and Ang Ⅱ + DHA (40 nmol/L) groups was significantly higher than that in the Ang Ⅱ + DHA (0 nmol/L) group (P ＜ 0.05). With the increase of DHA concentration, the expression levels of Collagen Ⅰ, TGF - β1, YAP1 and TAZ proteins in H9C2 cells significantly decreased (P ＜ 0.05). Compared with the Ang Ⅱ + DHA group, the expression levels of YAP1, TAZ, Collagen Ⅰ and TGF - β1 proteins significantly increased in the Ang Ⅱ + DHA + GA-017 group (P ＜ 0.05). Compared with the control group, the expression levels of YAP1, TAZ, Collagen Ⅰ and TGF - β1 proteins in the heart tissue of Ang Ⅱ group mice significantly increased (P ＜ 0.05), while DHA treatment reduced the protein expression of YAP1, TAZ, Collagen Ⅰ, and TGF - β1 (P ＜ 0.05). Compared with the Ang Ⅱ + DHA group, the expression of YAP1, TAZ, Collagen Ⅰ, and TGF - β1 proteins in the heart tissue of Ang Ⅱ + DHA + GA-017 group mice significantly increased (P ＜ 0.05). The results of PSR stainingshowed that the degree of left ventricular fibrosis in Ang Ⅱ group mice was significantly higher than that in the control group (P ＜ 0.05); On the contrary, DHA treatment reduced the degree of left ventricular fibrosis in Ang Ⅱ mice (P ＜ 0.05). Compared with the Ang Ⅱ + DHA group, the degree of left ventricular fibrosis in the Ang Ⅱ + DHA + GA-017 group significantly increased (P ＜ 0.05).

Conclusions DHA can improve Ang Ⅱ -induced cardiomyocyte fibrosis, and its mechanism of action may partly involve the inhibition of the Hippo signaling pathway.