自噬
细胞生物学
蛋白质降解
化学
ATG5型
激酶
蛋白激酶A
溶酶体
蛋白酶体
mTORC1型
安普克
内质网
生物
PI3K/AKT/mTOR通路
葛兰素史克-3
组织蛋白酶B
细胞内
p38丝裂原活化蛋白激酶
TFEB
作者
Yuan Liu,Congqing Hao,Wei Zhang,Yuzhou Liu,Sen Guo,Ran Li,Meng Peng,Yawei Xu,Xiaoxin Pei,Haibo Yang,Yin-tao Zhao
标识
DOI:10.1016/j.jare.2021.07.004
摘要
Abstract Introduction Leucine-rich repetitive kinase-2 (LRRK2) is a Parkinson's disease-related gene that also participates in many inflammatory diseases. However, the functional role of LRRK2 in cardiovascular disease is not clear. Objective In this study, we aimed to elucidate the role of LRRK2 in cardiac remodelling under pressure overload. Methods Aortic banding surgery was performed to induce cardiac remodelling in a LRRK2 knockout mouse model. A cardiomyocyte remodelling model was established by phenylephrine (PE) stimulation in neonatal rat cardiomyocytes. Results LRRK2 was upregulated in remodelled mouse hearts and cardiomyocytes. Cardiac hypertrophy, fibrosis and dysfunction were ameliorated in LRRK2 knockout mice. LRRK2 silencing protected against the PE-induced cardiomyocyte hypertrophic response, while LRRK2 over-expression worsened the PE-induced hypertrophic response in cardiomyocytes. Decreased autophagy was observed in remodelled cardiomyocytes, whereas LRRK2 silencing increased autophagy levels and LRRK2 overexpression reduced autophagy levels. The autophagy inhibitors 3-MA, bafilomycin and chloroquine reversed the protective effects of LRRK2 deficiency. The autophagy activator rapamycin reversed the deleterious effects of LRRK2 overexpression. We found that LRRK2 inhibited Bcl-2 phosphorylation, thus decreasing the phosphorylation of Beclin1. The protective effects of LRRK2 knockout were partly counteracted by Beclin1(+/−) in vivo and Beclin1 silencing in vitro. We also observed an interaction between LRRK2 and Rab7, an autolysosome degradation-associated protein, which caused Rab7 downregulation. Rab7 knockdown almost completely reversed LRRK2 silencing-induced protection of cardiomyocytes Conclusion LRRK2 deficiency protected against cardiac remodelling under pressure overload by increasing Bcl-2/Beclin1 and Rab7-regulated autophagy levels in the heart.
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