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Multi-Omics Analysis Combined with Machine Learning Identified FABP4 in Smooth Muscle Cells as a Pathogenic Factor in
Yinyu Wang1, Tingting Shang1, Rui Cai2
1Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, People's Republic of China.
Background:
Atherosclerosis is the pathological basis of coronary heart disease, stroke, and peripheral arterial disease. Smooth muscle cells (SMCs) play a crucial role in atherosclerotic pathogenesis. However, effective drugs and therapy targeting SMCs for treating atherosclerosis are still lacking.
Methods:
We utilized single-cell RNA sequencing (scRNA-seq) (GSE155512 and GSE159677) and array data (GSE43292 and GSE125771) to identify Scissor+ SMCs (SMCs positively associated with atherosclerosis) and Scissor- SMCs (SMCs negatively associated with atherosclerosis) by using Scissor package. We analyzed their functional changes, cell-cell communication, and differentiation potential. Machine learning techniques were employed to analyze the marker in SMCs of atherosclerosis. qRT-PCR was used to examine the expression of these genes in MOVAS stimulated by ox-LDL. Potential inhibitors of the identified proteins were predicted, and their binding sites were analyzed.
Results:
We identified 475 Scissor+ SMCs and 1363 Scissor- SMCs. Functional enrichment analysis revealed that Scissor+ SMCs exhibited downregulation of Rho-related pathways, while pro-inflammatory pathways were upregulated. Cell-cell communication analysis indicated tighter interactions between SMCs and endothelial cells. Differential expression analysis identified 20 genes highly expressed in both scRNA-seq and array data. The LASSO regression, random forest, support vector machine and receiver operating characteristic curve suggested a strong correlation between fatty acid-binding protein 4 (FABP4) and atherosclerosis. The qRT-PCR results showed that FABP4 was highly expressed in MOVAS stimulated by ox-LDL. Drug prediction revealed that (S)-RP-6306 acted as an inhibitor, via forming a polar bond with Arg-126. In vitro experiments confirmed that (S)-RP-6306 significantly reduced the expression of FABP4.
Conclusion:
Scissor+ SMCs differed significantly from Scissor- SMCs in cellular function, cell-cell communication, and differentiation potential. The high expression of FABP4 in this subgroup of SMCs presented a promising therapeutic target for atherosclerosis, with (S)-RP-6306 showing potential as a drug targeting FABP4.
Insights
Researchers identified specific smooth muscle cells (SMCs) linked to atherosclerosis. Fatty acid-binding protein 4 (FABP4) was a key marker, and a potential drug, (S)-RP-6306, effectively targeted FABP4 in studies.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Genomics
Background:
- Atherosclerosis, the underlying cause of cardiovascular diseases, involves smooth muscle cells (SMCs).
- Current therapeutic strategies targeting SMCs for atherosclerosis remain limited.
- Understanding SMC heterogeneity is crucial for developing effective treatments.
Purpose of the Study:
- To identify and characterize distinct subsets of SMCs in atherosclerosis.
- To uncover novel molecular markers and therapeutic targets within SMCs.
- To explore potential drug candidates for atherosclerosis treatment.
Main Methods:
- Single-cell RNA sequencing and array data analysis to classify SMCs.
- Functional enrichment, cell-cell communication, and differentiation potential analyses.
- Machine learning for marker identification and drug target prediction.
Main Results:
- Identification of Scissor+ SMCs (atherosclerosis-associated) and Scissor- SMCs.
- Scissor+ SMCs showed upregulated pro-inflammatory pathways and altered cell-cell interactions.
- Fatty acid-binding protein 4 (FABP4) was identified as a key marker, with (S)-RP-6306 showing inhibitory potential.
Conclusions:
- Distinct SMC subsets exhibit unique functional and communicational profiles in atherosclerosis.
- FABP4 represents a promising therapeutic target for atherosclerosis.
- (S)-RP-6306 demonstrates potential as a FABP4-targeting drug for atherosclerosis.
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