NDRG1 Regulates Iron Metabolism and Inhibits Pathologic Cardiac Hypertrophy

Background

Cardiac pathologic hypertrophy, a pathologic physiological alteration in many cardiovascular diseases, can progress to heart failure. The cellular biology underlying myocardial hypertrophy remains to be fully elucidated. Although N-myc downstream-regulated gene 1 (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 pathologic hypertrophy.

Method

Cardiomyocyte-specific NDRG1 knockout (KO) transgenic mice and NDRG1-AAV9 were used in mice. Angiotensin II (AngII) stimulation was applied to induce hypertrophy. Histologic, molecular, and RNA-sequencing analyses were performed, and ferroptosis markers and iron levels were studied. We used co-immunoprecipitation (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 pathologic hypertrophy induced by AngII stimulation. Conditional KO 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 remodelling induced by NDRG1 deficiency.

Conclusions

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