Key result
TIM50 overexpression alleviates cardiac hypertrophy and fibrosis in preclinical models by reducing oxidative stress.
Why the study?
The role of translocase of inner membrane 50 (TIM 50) in pathological cardiac hypertrophy was unknown.
Does TIM50 expression regulate pathological cardiac hypertrophy and fibrosis in mouse models?
Does TIM50 expression regulate pathological cardiac hypertrophy and fibrosis in mouse models?
TIM50 attenuates pathological cardiac hypertrophy by reducing oxidative stress, highlighting a novel potential therapeutic target for heart failure.
Background Translocase of inner membrane 50 ( TIM 50) is a member of the translocase of inner membrane ( TIM ) complex in the mitochondria. Previous research has demonstrated the role of TIM 50 in the regulation of oxidative stress and cardiac morphology. However, the role of TIM 50 in pathological cardiac hypertrophy remains unknown. Methods and Results In the present study we found that the expression of TIM 50 was downregulated in hypertrophic hearts. Using genetic loss‐of‐function animal models, we demonstrated that TIM 50 deficiency increased heart and cardiomyocyte size with more severe cardiac fibrosis compared with wild‐type littermates. Moreover, we generated cardiomyocyte‐specific TIM 50 transgenic mice in which the hypertrophic and fibrotic phenotypes were all alleviated. Next, we tested reactive oxygen species generation and the activities of the antioxidant enzymes superoxide dismutase and catalase, and also respiratory chain complexes I, II, and IV, finding that all the activities were regulated by TIM 50. Meanwhile, expression of the ASK 1‐ JNK /P38 axis was increased in TIM 50‐deficient mice, and TIM 50 overexpression decreased the activity of the ASK 1‐ JNK /P38 axis. Finally, we treated mice with the antioxidant N‐acetyl cysteine to reduce oxidative stress. After N‐acetyl cysteine treatment, the deteriorative hypertrophic and fibrotic phenotypes caused by TIM 50 deficiency were all remarkably reversed. Conclusions These data indicated that TIM 50 could attenuate pathological cardiac hypertrophy primarily by reducing oxidative stress. TIM 50 could be a promising target for the prevention and therapy of cardiac hypertrophy and heart failure.
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Tang et al. (2017) studied Pathological cardiac hypertrophy. TIM 50 deficiency or overexpression and N-acetyl cysteine vs. Wild-type littermates was evaluated on Hypertrophic and fibrotic phenotypes.
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