Angiotensin II-Induced Long Non-Coding RNA Alivec Regulates Chondrogenesis in Vascular Smooth Muscle Cells.

Vishnu Amaram Samara,Rama Natarajan,Linda Lanting,Amy Leung,Kenneth Stapleton,Maryam Abdollahi,Marpadga A Reddy,Rituparna Ganguly,Sadhan Das,Vinay Singh Tanwar

doi:10.3390/cells10102696

Vishnu Amaram Samara, Rama Natarajan + Show 8 more

Open Access

https://doi.org/10.3390/cells10102696

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Journal: Cells	Publication Date: Oct 9, 2021
Citations: 4	License type: CC BY 4.0

Affiliation: City of Hope, Central Drug Research Institute

Abstract

Long non-coding RNAs (lncRNAs) play key roles in Angiotensin II (AngII) signaling but their role in chondrogenic transformation of vascular smooth muscle cells (VSMCs) is unknown. We describe a novel AngII-induced lncRNA Alivec (Angiotensin II-induced lncRNA in VSMCs eliciting chondrogenic phenotype) implicated in VSMC chondrogenesis. In rat VSMCs, Alivec and the nearby gene Acan, a chondrogenic marker, were induced by growth factors AngII and PDGF and the inflammatory cytokine TNF-α. AngII co-regulated Alivec and Acan through the activation of AngII type1 receptor signaling and Sox9, a master transcriptional regulator of chondrogenesis. Alivec knockdown with GapmeR antisense-oligonucleotides attenuated the expression of AngII-induced chondrogenic marker genes, including Acan, and inhibited the chondrogenic phenotype of VSMCs. Conversely, Alivec overexpression upregulated these genes and promoted chondrogenic transformation. RNA-pulldown coupled to mass-spectrometry identified Tropomyosin-3-alpha and hnRNPA2B1 proteins as Alivec-binding proteins in VSMCs. Furthermore, male rats with AngII-driven hypertension showed increased aortic expression of Alivec and Acan. A putative human ortholog ALIVEC, was induced by AngII in human VSMCs, and this locus was found to harbor the quantitative trait loci affecting blood pressure. Together, these findings suggest that AngII-regulated lncRNA Alivec functions, at least in part, to mediate the AngII-induced chondrogenic transformation of VSMCs implicated in vascular dysfunction and hypertension.

Highlights

Cardiovascular diseases (CVDs), such as hypertension and atherosclerosis, are leading causes of morbidity and mortality worldwide [1]
We analyzed RNA-seq data previously generated in our laboratory from rat VSMCs (RVSMCs) treated with Angiotensin II (AngII) (100 nM, 3 h) [18] using STAR aligner and observed that a previously identified novel Long non-coding RNAs (lncRNAs), which we named Alivec, was highly induced by AngII (Figure 1A)
Combined RNA-seq and ChIP-seq data showed that the lncRNA Alivec locus overlaps with an AngII-induced H3K27ac enriched region (Figure 1B)

Summary

Introduction

Cardiovascular diseases (CVDs), such as hypertension and atherosclerosis, are leading causes of morbidity and mortality worldwide [1]. In CVD or vascular injury, dysregulated growth factor and AngII signaling promotes VSMCs to switch from a contractile to synthetic phenotype [3]. The synthetic phenotype manifests in increased VSMC proliferation, hypertrophy, migration, inflammation and the key processes associated with the pathogenesis of arterial stenosis/restenosis, hypertension and atherosclerosis [4,5,6,7]. The synthetic VSMCs tend to transform into chondrocyte-like cells, which promotes extracellular calcium deposition and vascular dysfunction associated with these pathologies [8,9,10]. The transcription factor (TF) Sox, which regulates chondrogenesis, is associated with VSMC synthetic/chondrocyte phenotype and promotes extra-cellular matrix (ECM) alterations and calcium deposition [11]. The mechanisms involved in AngII-mediated phenotypic transformation of VSMC to chondrocyte-like cells are not well understood

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