KIAA1429 and ALKBH5 Oppositely Influence Aortic Dissection Progression via Regulating the Maturation of Pri-miR-143-3p in an m6A-Dependent Manner.

Peng Wang,Shun Yuan,Qi Wu,Feng Shi,Min Zhang,Zhiwei Wang

doi:10.3389/fcell.2021.668377

Abstract

Despite decades of study into aortic dissection (AD), a lethal cardiovascular emergency due to a tear in the aorta intima or bleeding within the aortic wall, leading to the separation of the different layers of it, the factors that influence its progression and the deeper regulatory mechanisms remain poorly understood. Nowadays, with the maturity of N6-methyladenosine (m6A) sequence technology, m6A modification, one type of RNA epigenesis, has gradually become a new research hotspot for epigenetic molecular regulation. Especially recently, increasing evidence has revealed that m6A modification functions as a pivotal post-transcriptional modification to influence the progression of multiple diseases. Based on these findings, it is reasonable to speculate that m6A modification may affect the onset and progression of AD. To explore the validity of our conjecture and to elucidate its underlying molecular mechanism of action, we conducted the present study. In this study, we found that KIAA1429 is downregulated while ALKBH5 is upregulated in aortic tissues from AD patients. Furthermore, gain- and loss-of-function studies showed that KIAA1429 and ALKBH5 can oppositely regulate HASMC proliferation, HAEC apoptosis, and AD progression in AngII-infused mice. Mechanistically, we demonstrated that KIAA1429/ALKBH5-mediated m6A modifications can regulate the processing of pri-miR-143-3p through interacting with the microprocessor protein DGCR8, thus indirectly regulating the downstream target gene of mature miR-143-3p, DDX6, to perform their biological functions in vitro and in vivo. Our findings have revealed a novel connection between m6A modification and AD progression and may provide a novel molecular basis for subsequent researchers to search for novel therapeutic approaches to improve the health of patients struggling with AD.

Highlights

Aortic dissection (AD) is a lethal cardiovascular emergency due to a tear in the aorta intima or bleeding within the aortic wall, leading to the separation of the different layers of the aortic wall (Gawinecka et al, 2017; Tchana-Sato et al, 2018)
To identify whether m6A modification was involved in AD development, we initially measured the expression levels of multiple key genes related to m6A, as described in section “Introduction,” in 25 pairs of aorta tissues derived from donors and AD patients
It was observed that KIAA1429 was significantly downregulated while ALKBH5 was upregulated in the aorta specimens of AD patients compared to donors (Figure 1A and Supplementary Figure 1)

Summary

Introduction

Aortic dissection (AD) is a lethal cardiovascular emergency due to a tear in the aorta intima or bleeding within the aortic wall, leading to the separation of the different layers of the aortic wall (Gawinecka et al, 2017; Tchana-Sato et al, 2018). Despite decades of study into AD, the factors that influence its progression and the deeper regulatory mechanisms remain poorly understood. One of the prerequisites to the development of novel coping strategies for AD is to elucidate the underlying molecular mechanisms involved. According to the results of available studies, both decreased cell proliferation capacity of human aortic smooth muscle cells (HASMCs) and excessive apoptosis of human aortic endothelial cells (HAECs) in the arterial vascular wall are closely related to the development of AD (Lai et al, 2019; Song et al, 2019; Sun et al, 2020). Numerous studies have confirmed this conclusion, the molecular regulatory mechanisms involved in HASMC and HAEC dysfunction are not well investigated, especially epigenetic studies. At the RNA level, diverse types of posttranscriptional modifications have been recognized, among which N6-methyladenosine (m6A) RNA methylation is one of the most common modifications in eukaryote messenger RNAs (Desrosiers et al, 1974; Dominissini et al, 2012; Meyer et al, 2012)

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Conclusion