The Canadian journal of cardiology · 2024
NDRG1 Regulates Iron Metabolism and Inhibits Pathologic Cardiac Hypertrophy.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Yuan Jiali, Yin Chengye, Peng Hong, Fang Guojian, Mo Binfeng, Qin Xiji, Chen Yuhan, Wang Zhengshuai, Yu Yichi, Wang Yuepeng, Wang Qunshan
Аннотация
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.
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.