HDAC6 Negatively Regulates miR-155-5p Expression to Elicit Proliferation by Targeting RHEB in Microvascular Endothelial Cells under Mechanical Unloading.

Yixuan Wang,Honghui Wang,Lijun Zhang,Fei Shi,Liqun Xu,Shu Zhang,Xiaoyan Zhang,Zebing Hu,Xinsheng Cao,Gaozhi Li,Jingjing Dong

doi:10.3390/ijms221910527

Abstract

Mechanical unloading contributes to significant cardiovascular deconditioning. Endothelial dysfunction in the sites of microcirculation may be one of the causes of the cardiovascular degeneration induced by unloading, but the detailed mechanism is still unclear. Here, we first demonstrated that mechanical unloading inhibited brain microvascular endothelial cell proliferation and downregulated histone deacetylase 6 (HDAC6) expression. Furthermore, HDAC6 promoted microvascular endothelial cell proliferation and attenuated the inhibition of proliferation caused by clinorotation unloading. To comprehensively identify microRNAs (miRNAs) that are regulated by HDAC6, we analyzed differential miRNA expression in microvascular endothelial cells after transfection with HDAC6 siRNA and selected miR-155-5p, which was the miRNA with the most significantly increased expression. The ectopic expression of miR-155-5p inhibited microvascular endothelial cell proliferation and directly downregulated Ras homolog enriched in brain (RHEB) expression. Moreover, RHEB expression was downregulated under mechanical unloading and was essential for the miR-155-5p-mediated promotion of microvascular endothelial cell proliferation. Taken together, these results are the first to elucidate the role of HDAC6 in unloading-induced cell growth inhibition through the miR-155-5p/RHEB axis, suggesting that the HDAC6/miR-155-5p/RHEB pathway is a specific target for the preventative treatment of cardiovascular deconditioning.

Highlights

Mechanical unloading implies decreasing the load on each part of the body, due to microgravity environments or prolonged −6◦ head-down bed rest, and can induce almost all human physiological system disorders, especially cardiovascular deconditioning [1,2].Cardiovascular deconditioning is partly secondary to the transfer of fluid from the lower extremities to the cardiothoracic area in the initial period of weightlessness exposure, the most serious symptoms of which are orthostatic intolerance, decreased exercise capacity, and increased resting heart rate, which prevent further interstellar missions and cause a major global public health problem [1,3]
To investigate whether mechanical unloading inhibited proliferation in microvascular endothelial cells, the expression of proliferating cell nuclear antigen (PCNA) was examined by Western blotting after clinorotation for 48 h, and the results showed that PCNA
histone deacetylase 6 (HDAC6) may be involved in regulating (Figures 1E and S1B). These findings indicate that HDAC6 may be involved in microvascular endothelial cell proliferation under mechanical unloadingunloading conditions

Summary

Introduction

Mechanical unloading implies decreasing the load on each part of the body, due to microgravity environments or prolonged −6◦ head-down bed rest, and can induce almost all human physiological system disorders, especially cardiovascular deconditioning [1,2].Cardiovascular deconditioning is partly secondary to the transfer of fluid from the lower extremities to the cardiothoracic area in the initial period of weightlessness exposure, the most serious symptoms of which are orthostatic intolerance, decreased exercise capacity, and increased resting heart rate, which prevent further interstellar missions and cause a major global public health problem [1,3]. Mechanical unloading implies decreasing the load on each part of the body, due to microgravity environments or prolonged −6◦ head-down bed rest, and can induce almost all human physiological system disorders, especially cardiovascular deconditioning [1,2]. Since the microvascular endothelium plays a vital role in the regulation of vascular homeostasis and local blood flow, microvascular endothelial dysfunction is related to cardiovascular disorders [4,8]. Previous studies have shown that unloading conditions inhibit the proliferation of microvascular endothelial cells and promote apoptosis associated with the impairment of endothelial function and might contribute to the cardiovascular deconditioning induced by weightlessness [4,9]

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Results

Discussion

Conclusion