Leucine-rich repeat kinase-2 deficiency protected against cardiac remodelling in mice via regulating autophagy formation and degradation,Journal of Advanced Research

当前位置： X-MOL 学术 › J. Adv. Res. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Leucine-rich repeat kinase-2 deficiency protected against cardiac remodelling in mice via regulating autophagy formation and degradation
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2021-07-10 , DOI: 10.1016/j.jare.2021.07.004
Yuan Liu ₁ , Congqing Hao ₁ , Wei Zhang ₂ , Yuzhou Liu ₁ , Sen Guo ₁ , Ran Li ₁ , Meng Peng ₁ , Yawei Xu ₁ , Xiaoxin Pei ₁ , Haibo Yang ₁ , Yintao Zhao ₁

Affiliation

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.

中文翻译：

富含亮氨酸的重复激酶2缺乏通过调节自噬形成和降解来保护小鼠免受心脏重塑

介绍

富含亮氨酸的重复激酶 2 (LRRK2) 是帕金森病相关基因，也参与许多炎症性疾病。然而，LRRK2 在心血管疾病中的功能作用尚不清楚。

客观的

在这项研究中，我们旨在阐明 LRRK2 在压力过载下心脏重塑中的作用。

方法

在 LRRK2 基因敲除小鼠模型中进行主动脉束带手术以诱导心脏重塑。通过苯肾上腺素（PE）刺激新生大鼠心肌细胞建立心肌细胞重塑模型。

结果

LRRK2 在重塑的小鼠心脏和心肌细胞中上调。LRRK2基因敲除小鼠的心脏肥大、纤维化和功能障碍得到改善。LRRK2 沉默保护免受 PE 诱导的心肌细胞肥大反应，而 LRRK2 过表达恶化了 PE 诱导的心肌细胞肥大反应。在重塑的心肌细胞中观察到自噬减少，而 LRRK2 沉默增加了自噬水平，而 LRRK2 过表达降低了自噬水平。自噬抑制剂 3-MA、巴弗洛霉素和氯喹逆转了 LRRK2 缺乏的保护作用。自噬激活剂雷帕霉素逆转了 LRRK2 过表达的有害影响。我们发现 LRRK2 抑制 Bcl-2 磷酸化，从而降低 Beclin1 的磷酸化。体内和 Beclin1体外沉默。我们还观察到 LRRK2 和 Rab7 之间的相互作用，Rab7 是一种自溶酶体降解相关蛋白，导致 Rab7 下调。Rab7 敲低几乎完全逆转了 LRRK2 沉默诱导的心肌细胞保护