Table 1 Novel Findings of the Integrative Pathway Analysis of moxLDL-induced SMC Phenotype Transformation
Theme | Novel Findings |
|---|---|
Cholesterol synthesis & transport | The observation of upregulated cholesterol biosynthesis coupled with a dysregulation of the reverse cholesterol transport pathway in moxLDL-induced SMC may promote the accumulation of cholesterol and cholesterol esters in the cells, and facilitate foam cell formation during atherogenesis |
GPCR signaling | Observed GPCR signaling may have a role in SMC transformation. GPCR signaling following activation via inflammatory or other microenvironmental stimuli have been implicated in responses, such as change of cell-to-cell and cell-to-matrix adhesion, matrix remodeling, cell proliferation, migration, and immune cell trafficking and regulation. The activation of GPCR pathways may thus play a role in the initiation of SMC dedifferentiation and phenotype transformation. |
Cytokine & growth factor | Potential role for IL12, IFN-α, HGF, CSF3 and VEGF signaling in SMC phenotype transformation. |
Cell cycle control | Up-regulation of HBP1, a repressor of cyclin D1 and CDKN1B, suggests a negative feedback loop auto-triggered by the up-regulation of the core cell cycle machinery during SMC phenotype transformation. |
Cell differentiation | The deregulation of the ID2 and ZEB1 regulators of differentiation during SMC phenotype transformation is consistent with the onset of SMC de-differentiation. |
miRNA & de-differentiation | Potential role of miRNAs in the regulation of SMC phenotype transformation via interactions with the IFN-γ pathway. |
Nexus genes in complex networks | Several “nexus” genes, including the components of a multi-subunit complex involved in the terminal stages of cholesterol synthesis, miRNAs (e.g. miR-203, miR-511, miR-590-3p, miR- 346*/miR-1207-5p/miR-4763-3p), members of the GPCR family of proteins (e.g. GPR1, GPR64, GPRC5A,GPR171, GPR176, GPR32, GPR25, and GPR124) and signal transduction pathways were observed. These genes may play important roles in VSMC phenotype transformation and in the pathogenesis of AT and coronary artery disease and may provide novel targets for drug discovery. |