Silencing PACS2 attenuates cardiac hypertrophy by inhibiting ferroptosis via activating SIRT1.

BACKGROUND

Cardiac hypertrophy plays an important role in organ damage caused by hypertension and may progress into heart failure. This study investigated the function and underlying mechanisms of phosphofurin acidic cluster sorting protein 2 (PACS2) in relation to cardiac hypertrophy.

MATERIALS AND

METHODS

To create both in vitro and in vivo models, Ang-II stimulation and transverse aortic constriction (TAC) were employed. The cross-sectional area of cardiomyocytes was measured through immunofluorescence, while gene and protein expression levels were analyzed using RT-qPCR and Western blot. Myocardial damage was evaluated by H&E staining, and cardiac function was determined assessed through echocardiography.

RESULTS

Ang-II treatment triggered hypertrophic changes, increased expression levels of ANP, BNP, Myh7, Acta1 and PACS2, and activated oxidative stress along with ferroptosis in cardiomyocytes. Silencing of PACS2 led to a decrease in hypertrophy, oxidative stress, and ferroptosis, while promoting the nuclear translocation of Nrf2 and activating the Nrf2/HO-1 signaling pathway both in Ang-II-treated cardiomyocytes and in TAC rats. Ang-II treatment caused a decline in SIRT1 expression level, which was restored upon PACS2 inhibition. The protective benefits of PACS2 knockdown were partially negated by the inhibition of SIRT1. In animal models, PACS2 silencing alleviated myocardial damage and hypertrophy in TAC rats, which was accompanied by increased activation of Nrf2/HO-1 and an inhibition in ferroptosis, both of which were rescued by SIRT1 inhibition. Mechanistically, PACS2 regulated SIRT1 expression through its interaction with the transcription factor HIC1.

CONCLUSION

Silencing of PACS2 attenuates cardiac hypertrophy caused by Ang-II in vitro and TAC in vivo by repressing oxidative stress and ferroptosis, which is facilitated by the activation of the Nrf2/HO-1 signaling pathway through the enhancement of SIRT1 expression via its interaction with HIC1.