Key Takeaways & Executive Findings
- •• IRX3 is highly expressed in brown adipose tissue and its expression increases during brown adipocyte differentiation, suggesting a role in browning. • IRX3 regulates browning by targeting retinol saturase (RetSat), as knockdown of IRX3 reduces RetSat and browning markers, while RetSat overexpression rescues the browning phenotype. • In diabetic perivascular adipose tissue, browning-related genes (UCP1, PRDM16, CIDEA) are downregulated, and IRX3 expression is reduced, implicating IRX3 in vascular injury. • Single-cell analysis reveals IRX3 is specifically expressed in adipocyte subpopulations, and its modulation may offer a therapeutic strategy for vascular injury by promoting perivascular adipose tissue browning.
Abstract
BACKGROUND: Vascular injury-related diseases have garnered significant attention in the medical field, and the browning of perivascular adipose tissue is closely linked to these diseases. However, the regulatory mechanisms of specific genes involved in this process remain unclear. OBJECTIVE: To investigate the potential mechanism by which iroquois homeobox 3 regulates the browning of perivascular adipose tissue in vascular injury. METHODS: The perivascular adipose tissue-related single-cell sequencing data matrix GSE275779 was analyzed to investigate the expression levels and functions of iroquois homeobox 3 in various cell subpopulations. In conjunction with adipocyte-related microarray and sequencing data GSE44059, GSE7032, GSE185518, and GSE168387, differentially expressed genes were identified, and the expression level of iroquois homeobox 3 during the differentiation of browning adipocytes was validated. The downstream target genes of iroquois homeobox 3 were screened using the msigdb database and the ChIP-seq database GTRD. By disrupting iroquois homeobox 3 and overexpressing retinol saturase in adipocyte precursor cells, the mRNA and protein expression levels of browning-related genes were detected by qPCR and western blot. RESULTS AND CONCLUSION: Bioinformatics analysis showed that adipocyte characteristic factors such as PR domain containing 16, cell death-inducing DFFA-like effector A, and uncoupling protein 1 were significantly downregulated in perivascular adipose tissue of diabetic patients, and these genes are involved in adipose browning. Combined with high-throughput sequencing data analysis, it was found that iroquois homeobox 3 is highly expressed in brown adipose tissue and participates in brown adipocyte differentiation. Further screening identified retinol saturase as a downstream target gene of iroquois homeobox 3, and its level was differentially expressed during brown adipocyte differentiation. In mature brown adipocytes, knockdown of iroquois homeobox 3 led to decreased expression of retinol saturase and browning-related markers (uncoupling protein 1, peroxisome proliferator-activated receptor gamma coactivator 1 alpha, PR domain containing 16). In the retinol saturase rescue experiment, overexpression of retinol saturase significantly upregulated the protein levels of browning-related markers but did not affect the expression of iroquois homeobox 3. This study preliminarily reveals the potential mechanism by which iroquois homeobox 3 regulates perivascular adipose tissue browning during vascular injury.
1. Introduction
Vascular injury is a pathological basis for various cardiovascular diseases such as atherosclerosis and hypertension [1-2]. Previous research on vascular injury has mainly focused on vascular endothelial cells [3]. However, recent studies have shown that perivascular adipose tissue (PVAT) dysfunction is involved in vascular injury [4-5]. For instance, renal denervation alleviates vascular remodeling in spontaneously hypertensive rats by modulating PVAT [6]. PVAT surrounds most blood vessels and is a fat depot composed of white, beige, and brown adipose tissue [7]. It has been reported that high-fat diet and other external stimuli induce the transformation of brown adipose tissue to a white phenotype, releasing inflammatory factors and leading to vascular injury [8]. Conversely, browning of PVAT, i.e., the transition from white to brown phenotype, helps reduce inflammation and promote vascular remodeling [9-10]. Therefore, promoting PVAT browning may be an effective strategy to alleviate vascular injury.
Iroquois homeobox gene 3 (IRX3) is a transcription factor of the Iroquois homeobox gene family. Studies have shown that IRX3 has a protective role in cardiovascular diseases [11-13] and is closely associated with adipose tissue [14-15], but the underlying mechanism remains unclear. For example, in patients with aortic stenosis undergoing transcatheter aortic valve implantation, those with higher blood IRX3 methylation levels had significantly improved survival [11]. Given the importance of PVAT browning in vascular injury, this study aims to investigate the potential mechanism by which IRX3 regulates PVAT browning in the context of vascular injury.
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Hu Xiaoyong, Song Qianhua, Yang Zhaoying, Tang Rui, Li Hongjian (2026). Potential mechanism by which iroquois homeobox 3 regulates the browning of perivascular adipose tissue in vascular injury. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21228
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Frequently Asked Questions
What is the role of IRX3 in perivascular adipose tissue browning?
IRX3 is a transcription factor that promotes browning of perivascular adipose tissue by regulating the expression of retinol saturase (RetSat). Knockdown of IRX3 reduces RetSat and browning markers, while overexpression of RetSat rescues the browning phenotype, indicating that IRX3 acts through RetSat to mediate browning.
How does IRX3 affect vascular injury?
IRX3 promotes browning of perivascular adipose tissue, which reduces inflammation and promotes endothelial repair, thereby protecting against vascular injury. In diabetic conditions, IRX3 expression is reduced, leading to impaired browning and increased vascular injury.
What methods were used in this study?
The study utilized bioinformatics analysis of single-cell RNA sequencing data (GSE275779) and microarray datasets (GSE44059, GSE7032, GSE185518, GSE168387), along with ChIP-seq database GTRD and msigdb for target gene prediction. Functional validation was performed in 3T3-L1 adipocytes using qPCR and western blot after knockdown of IRX3 and overexpression of RetSat.
What are the key findings of this study?
Key findings include: IRX3 is highly expressed in brown adipose tissue and increases during differentiation; IRX3 regulates browning by targeting RetSat; in diabetic PVAT, browning genes are downregulated; and IRX3 knockdown reduces browning markers, while RetSat overexpression rescues the phenotype.
What is the clinical significance of this research?
This research provides insights into the molecular mechanisms of vascular injury and suggests that targeting IRX3 or RetSat could be a therapeutic strategy to promote PVAT browning and protect against vascular injury in conditions like hypertension and atherosclerosis.
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