Mst1 inhibits CMECs autophagy and participates in the development of diabetic coronary microvascular dysfunction.

Jie Lin,Dongdong Sun,Wanrong Man,Tingting Wang,Rongqing Zhang,Mingming Zhang,Yu Duan,Jianqiang Hu,Bin Wu,Lei Zhang,Lei Sun,Congye Li,Jiaxu Feng,Haichang Wang

doi:10.1038/srep34199

Jie Lin, Dongdong Sun + Show 12 more

Open Access

https://doi.org/10.1038/srep34199

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Journal: Scientific Reports	Publication Date: Sep 29, 2016
Citations: 36	License type: CC BY 4.0

Affiliation: Air Force Medical University, Xijing Hospital

Abstract

Cardiovascular complications account for a substantial proportion of morbidity and mortality in diabetic patients. Abnormalities of cardiac microvascular endothelial cells (CMECs) lead to impaired cardiac microvascular vessel integrity and subsequent cardiac dysfunction, underlining the importance of coronary microvascular dysfunction. In this study, experimental diabetes models were constructed using Mst1 transgenic, Mst1 knockout and sirt1 knockout mice. Diabetic Mst1 transgenic mice exhibited impaired cardiac microvessel integrity and decreased cardiac function. Mst1 overexpression deceased CMECs autophagy as evidenced by decreased LC3 expression and enhanced protein aggregation when subjected to high glucose culture. Mst1 knockout improved cardiac microvessel integrity and enhanced cardiac functions in diabetic mice. Mst1 knockdown up-regulated autophagy as indicated by more typical autophagosomes and increased LC3 expression in CMECs subjected to high glucose cultures. Mst1 knockdown also promoted autophagic flux in the presence of bafilomycin A1. Mst1 overexpression increased CMECs apoptosis, whereas Mst1 knockout decreased CMECs apoptosis. Sirt1 knockout abolished the effects of Mst1 overexpression in cardiac microvascular injury and cardiac dysfunction. In conclusion, Mst1 knockout preserved cardiac microvessel integrity and improved cardiac functions in diabetic mice. Mst1 decreased sirt1 activity, inhibited autophagy and enhanced apoptosis in CMECs, thus participating in the pathogenesis of diabetic coronary microvascular dysfunction.

Highlights

Mammalian ste20-like kinase 1 (Mst1) is a serine-threonine kinase that has been implicated in diverse biological functions, including autophagy, apoptosis and oxidative stress[7,8,9]
Mst[1] has been reported to promote cardiac dysfunction in mice subjected to myocardial infarction (MI) through inhibition of autophagy[10]
Diabetes led to impaired cardiac systolic function as manifested by decreases in left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS), the effects of which were significantly alleviated by Mst[1] knockout (Fig. 1B–D)

Summary

Introduction

Mammalian ste20-like kinase 1 (Mst1) is a serine-threonine kinase that has been implicated in diverse biological functions, including autophagy, apoptosis and oxidative stress[7,8,9]. Mst[1] has been reported to promote cardiac dysfunction in mice subjected to myocardial infarction (MI) through inhibition of autophagy[10]. Our previous study demonstrated that up-regulating autophagy through Mst[1] inhibition alleviates postinfarction cardiac dysfunction[11]. Mst[1] contains a ste20-related kinase catalytic domain in the amino-terminal segment followed by a regulatory domain at the COOH terminus[10]. Mst[1] can directly inhibit the activity of silent information regulator 1 (sirt1)[12]. The direct role of Mst1/sirt[1] signaling in the development of coronary microvascular damage in diabetes remains unknown. The objective of the present study was to investigate the precise involvement of autophagy and the underlying mechanisms in the pathogenesis of coronary microvascular disease in diabetes

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