Protein kinase WEE1 promotes cardiomyocytes ferroptosis and cardiac hypertrophy via the NF-κB/LCN2 axis.

Abstract

Under conditions of chronic pressure overload, cardiac hypertrophy can progressively develop into arrhythmias and heart failure, and in severe cases, may lead to sudden death. Previous studies have indicated that protein kinases play significant roles in cardiovascular diseases. This study aims to elucidate the function of the WEE1 G₂ checkpoint kinase (WEE1) in the progression of myocardial hypertrophy. We evaluated the expression of WEE1 in the hearts of mice with transverse aortic constriction (TAC). The functional role of WEE1 was investigated using siWEE1 in an angiotensin II (Ang II)-induced cardiomyocyte hypertrophy model. Furthermore, the contribution of WEE1 to cardiac hypertrophy was assessed in TAC mice via intraperitoneal administration of Adavosertib (WEE1-specific inhibitor). RNA-sequencing (RNA-seq) was employed to identify the downstream effector molecules of WEE1 in cardiomyocytes. The expression of both phosphorylated WEE1 and WEE1 was upregulated in hearts subjected to transverse aortic constriction and in cardiac cells treated with angiotensin II. Knockdown of WEE1 effectively alleviated Ang II-induced cardiac cell hypertrophy. Furthermore, application of the specific inhibitor Adavosertib significantly attenuated cardiac cell hypertrophy and improved cardiac function. Mechanistic studies revealed that WEE1 promotes the translocation of the transcription factor P65 from the cytoplasm to the nucleus, thereby activating the nuclear factor κB (NF-κB) signaling pathway, which ultimately upregulates the transcriptional level of Lipocalin2 (LCN2). LCN2 mediates the process of ferroptosis in cardiac cells by binding to the ferroptosis receptor solute carrier family 22 member 17 (SLC22A17), thereby inducing cardiac hypertrophy. Our findings indicate that WEE1 exacerbates cardiac hypertrophy by activating the NF-κB signaling pathway, which upregulates LCN2 expression and subsequently aggravates ferroptosis in cardiac cells. Inhibition of WEE1 significantly improves cardiac function, highlighting its potential value as a therapeutic target of cardiac hypertrophy.