NDRG1 regulates iron metabolism and inhibits pathological cardiac hypertrophy.

Abstract

Background: Cardiac pathological hypertrophy, a pathological physiological alteration in many cardiovascular diseases, can progress to heart failure. The cellular biology underlying myocardial hypertrophy remains to be fully elucidated. While NDRG1 has been reported to participate in cellular proliferation, differentiation, and cellular stress responses, its role in cardiac diseases remains unexplored. Here, we investigated the role of NDRG1 in pathological hypertrophy.

Method: Cardiomyocyte-specific-NDRG1 knockout (KO) transgenic mice and NDRG1-AAV9 were used in mice. Angiotensin II (AngII) stimulation were applied to induce hypertrophy. Histological, molecular, and RNA-sequencing analyses were performed, and ferroptosis markers and iron levels were studied. We used co-IP and application of iron chelator to further studied the mechanisms of NDRG1 in cardiac hypertrophy.

Results: We found that NDRG1 expression is decreased in pathological hypertrophy induced by AngII stimulation. Conditional knockout of NDRG1 in mouse cardiomyocytes led to progressive cardiac hypertrophy and heart failure. Cardiomyocyte-specific overexpression of NDRG1 via AAV9 significantly reversed AngII-induced ventricular hypertrophy and fibrosis. Mechanistically, NDRG1-deficient cardiomyocytes exhibited iron overload and increased ferroptosis, accompanied by elevated levels of reactive oxygen species (ROS) and lipid peroxidation. Subsequently, we confirmed the involvement of NDRG1 in regulating ferroptosis and iron metabolism in myocardial cells. Finally, we identified an interaction between NDRG1 and transferrin in cells. The iron chelator Dp44mT effectively reduced myocardial iron overload and ventricular remodeling induced by NDRG1 deficiency.

Conclusion: These findings highlight NDRG1's critical role in iron metabolism and ferroptosis in cardiomyocytes, suggesting that NDRG1 or iron metabolism may serve as therapeutic targets for cardiac hypertrophy.