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lncRNA HOTAIRM1 Activated by HOXA4 Drives HUVEC Proliferation Through Direct Interaction with Protein Partner HSPA5
Yu Zhou1,2, Qiang Wu3, Xiangshu Long2
1Medical College, Guizhou University, Guiyang, 550025, Guizhou, China.
Insights
Long non-coding RNA HOTAIRM1 is upregulated in atherosclerosis and impacts endothelial cell proliferation and apoptosis. This study reveals a regulatory circuit involving HOXA4, HOTAIRM1, and HSPA5, offering potential therapeutic targets for cardiovascular disease.
Area of Science:
- Molecular Cardiology
- RNA Biology
- Atherosclerosis Pathogenesis
Background:
- Atherosclerosis (AS) remains a leading cause of cardiovascular mortality despite progress in understanding its pathogenesis.
- Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators in AS development.
- The specific role of HOTAIRM1 in human umbilical vein endothelial cells (HUVECs) and AS remains largely unexplored.
Purpose of the Study:
- To investigate the function and mechanism of lncRNA HOTAIRM1 in HUVECs under atherosclerotic conditions.
- To elucidate the regulatory network involving HOTAIRM1, HOXA4, and HSPA5 in endothelial cell biology.
- To identify potential molecular targets for AS therapy.
Main Methods:
- Quantitative real-time PCR to assess HOTAIRM1 expression in HUVECs stimulated with oxidized low-density lipoprotein (ox-LDL).
- Functional assays including cell proliferation and apoptosis assays following HOTAIRM1 knockdown.
- Chromatin immunoprecipitation (ChIP) assays to determine HOXA4 binding to the HOTAIRM1 promoter.
- RNA immunoprecipitation (RIP) assays to investigate the interaction between HOTAIRM1 and HSPA5.
Main Results:
- HOTAIRM1 expression was significantly upregulated in HUVECs upon ox-LDL stimulation, suggesting its involvement in AS.
- HOTAIRM1 knockdown inhibited HUVEC proliferation and promoted apoptosis, both in the presence and absence of ox-LDL.
- HOXA4 directly activated HOTAIRM1 transcription, forming a positive feedback loop, and HOTAIRM1 interacted with HSPA5 in a transcription-dependent manner.
- HSPA5 overexpression partially rescued the inhibitory effects of HOTAIRM1 depletion on HUVEC proliferation.
Conclusions:
- The study identifies a novel regulatory axis comprising HOXA4, HOTAIRM1, and HSPA5 that modulates HUVEC proliferation.
- HOTAIRM1 plays a critical role in endothelial cell function relevant to atherosclerosis.
- The HOXA4-HOTAIRM1-HSPA5 pathway represents a promising target for developing novel therapeutic strategies against atherosclerosis.
Abstract:
Despite the substantial progress in deciphering the pathogenesis of atherosclerosis (AS), cardiovascular mortality is still increasing. Therefore, atherosclerotic cardiovascular disease remains a sweeping epidemic that jeopardizes human health. Disentangling the molecular underpinnings of AS is imperative in the molecular cardiology field. Overwhelming evidence has indicated that the recognition of a fascinating class of players, known as long non-coding RNAs (lncRNAs), provides causality for coordinating AS. However, the function and mechanism of HOTAIRM1 are still poorly understood in human umbilical vein endothelial cells (HUVECs) and AS. Herein, we primarily underscored that lncRNA HOTAIRM1 is potentially responsible for AS; as such, it was dramatically up-regulated in HUVECs upon ox-LDL stimulation. Functionally, HOTAIRM1 knockdown attenuated HUVEC proliferation and potentiated apoptosis in the absence and presence of ox-LDL. Furthermore, HOTAIRM1 was preferentially located in the nuclei of HUVECs. Mechanistically, HOXA4 is directly bound to the HOTAIRM1 promoter and activated its transcription. Of note, a positive feedback signaling between HOXA4 and HOTAIRM1 was determined. Intriguingly, the interplay between HOTAIRM1 and HSPA5 occurred in an RNA-binding protein pattern and a transcription-dependent regulatory manner. In addition, HSPA5 overexpression partially antagonized HUVEC proliferation inhibition of HOTAIRM1 depletion. Taken together, our findings delineate a pivotal functional interaction among HOXA4, HOTAIRM1, and HSPA5 as a novel regulatory circuit for modulating HUVEC proliferation. An in-depth investigation of the HOXA4-HOTAIRM1-HSPA5 axis promises to yield significant breakthroughs in identifying the molecular mechanisms governing AS and developing therapeutic avenues for AS.
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