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Identification of the Hub Gene LDB3 in Stanford Type A Aortic Dissection Based on Comprehensive Bioinformatics
Xinyi Liu1, Xing Liu2, Bin Wan3,4
1Department of Cardiovascular Surgery, Beijing Aortic Disease Center, Beijing Anzhen Hospital of Capital Medical University, Beijing, China.
Insights
The study reveals LIM domain binding 3 (LDB3) is a key gene in Stanford type A aortic dissection (TAAD) progression. Reduced LDB3 expression in TAAD tissues suggests its crucial role in this life-threatening disease.
Area of Science:
- Cardiovascular Biology
- Genetics
- Molecular Medicine
Background:
- Stanford type A aortic dissection (TAAD) is a critical cardiovascular condition with significant mortality.
- Understanding the molecular mechanisms underlying TAAD progression is essential for developing effective treatments.
Purpose of the Study:
- To investigate the role of LIM domain binding 3 (LDB3) as a potential key regulator in the pathogenesis of TAAD.
- To identify novel genetic markers and molecular players involved in TAAD.
Main Methods:
- Bioinformatic analysis of Gene Expression Omnibus datasets to identify TAAD-related hub genes.
- Assessment of LDB3 single nucleotide polymorphisms (SNPs) in the UK Biobank cohort.
- Western blotting and immunofluorescence to evaluate LDB3 expression in cellular and animal models of TAAD.
Main Results:
- LDB3 and tissue inhibitor of metalloproteinase-1 (TIMP1) were identified as significant hub genes in TAAD.
- LDB3 expression was found to be downregulated in TAAD tissues and Angiotensin II-stimulated human aortic vascular smooth muscle cells (HA-VSMC).
- Six LDB3 SNPs were significantly associated with aortic aneurysm and dissection, and reduced LDB3 expression correlated with altered intercellular connections in HA-VSMC.
Conclusions:
- The study identifies LDB3 as a novel and crucial gene in the progression of Stanford type A aortic dissection.
- Downregulation of LDB3 and its association with specific SNPs suggest a potential genetic predisposition and molecular pathway involved in TAAD.
- LDB3's role in smooth muscle cells and its alteration under pathological conditions highlight its importance in maintaining aortic integrity.
Abstract:
Stanford type A aortic dissection (TAAD) is a life-threatening disease. This study explored the role of LIM domain binding 3 (LDB3) in TAAD progression. Four datasets from the Gene Expression Omnibus were analyzed to identify TAAD-related hub genes. LDB3 single nucleotide polymorphisms (SNPs) were assessed in the UK Biobank. Western blotting and immunofluorescence detected LDB3 expression in angiotensin II (Ang II) stimulated human aortic vascular smooth muscle cells (HA-VSMC), human samples, and a murine model. Bioinformatics identified tissue inhibitor of metalloproteinase-1 (TIMP1) and LDB3 as TAAD hub genes. TIMP1 was expressed in macrophages, mesenchymal cells, and smooth muscle cells, while LDB3 was mostly expressed in smooth muscle cells. Validation showed TIMP1 was upregulated and LDB3 downregulated in TAAD. Six LDB3 SNPs were associated with aortic aneurysm and dissection in the UK Biobank. In human and murine samples, LDB3 expression was reduced in diseased tissues and co-localized with smooth muscle. Ang II-stimulated HA-VSMC exhibited LDB3 reduction and altered intercellular connections. The aforementioned findings suggest that the newly identified gene LDB3 is crucial in the progression of TAAD.
