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Upregulated miR-18a-5p in Colony Forming Unit-Hill's in Subclinical Cardiovascular Disease and Metformin Therapy;
Jason Phowira1,2, Fahad W Ahmed1,3,4, Sherin Bakhashab5
1Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Insights
MicroRNA-18a-5p is upregulated in type 1 diabetes mellitus (T1DM), contributing to atherosclerosis. Metformin reduces miR-18a-5p, improving vascular health markers and offering a potential therapeutic target for subclinical cardiovascular disease.
Area of Science:
- Cardiovascular Research
- Endocrinology
- Molecular Biology
Background:
- Colony forming unit-Hill's (CFU-Hill's) are hematopoietic stem cells crucial for neovasculogenesis and vascular health.
- Type 1 diabetes mellitus (T1DM) is associated with inflammation, endothelial dysfunction, and reduced CFU-Hill's, indicating subclinical cardiovascular disease (CVD).
- Overexpression of miR-18a-5p has been linked to pro-atherogenic effects in animal models.
Purpose of the Study:
- To investigate the role of miR-18a-5p in CFU-Hill's colonies within T1DM.
- To evaluate the cardioprotective effects of metformin in T1DM patients with subclinical CVD.
- To identify miR-18a-5p as a potential biomarker for T1DM and subclinical CVD.
Main Methods:
- Analysis of miR-18a-5p expression in CFU-Hill's from T1DM patients.
- Correlation analysis between miR-18a-5p levels and various cellular and inflammatory markers (CFU-Hill's, CD34+, CD34+CD133+, IL-10, CRP, VEGF-D, thrombomodulin).
- Receiver operating characteristic (ROC) curve analysis to assess biomarker potential.
- Ingenuity pathway analysis to identify miR-18a-5p and metformin targets.
Main Results:
- miR-18a-5p was significantly upregulated in T1DM patients.
- Metformin treatment reduced miR-18a-5p levels to healthy control (HC) levels.
- miR-18a-5p showed inverse correlations with CFU-Hill's and progenitor cells, and positive correlations with inflammatory markers.
- ROC analysis confirmed miR-18a-5p as a biomarker for T1DM and subclinical CVD at pre-diabetes HbA1c levels.
- Ingenuity pathway analysis revealed miR-18a-5p inhibits key growth factor and signaling pathways, while metformin upregulates them.
Conclusions:
- Upregulated miR-18a-5p plays a pro-atherogenic role in subclinical CVD associated with T1DM.
- Metformin demonstrates cardioprotective effects by downregulating miR-18a-5p and modulating its target genes.
- miR-18a-5p is a promising biomarker for T1DM and associated subclinical CVD, with identified target genes offering potential therapeutic avenues.
Abstract:
Colony forming unit-Hill's (CFU-Hill's) colonies are hematopoietic-derived cells that participate in neovasculogenesis and serve as a biomarker for vascular health. In animals, overexpression of miR-18a-5p was shown to be pro-atherogenic. We had shown that well-controlled type 1 diabetes mellitus (T1DM) is characterized by an inflammatory state, endothelial dysfunction, and reduced number of CFU-Hill's, a model of subclinical cardiovascular disease (CVD). MERIT study explored the role of miR-18a-5p expression in CFU-Hill's colonies in T1DM, and the cardioprotective effect of metformin in subclinical CVD. In T1DM, miR-18a-5p was significantly upregulated whereas metformin reduced it to HC levels. MiR-18a-5p was inversely correlated with CFU-Hill's colonies, CD34+, CD34+CD133+ cells, and positively with IL-10, C-reactive protein, vascular endothelial growth factor-D (VEGF-D), and thrombomodulin. The receiver operating characteristic curve demonstrated, miR-18a-5p as a biomarker of T1DM, and upregulated miR-18a-5p defining subclinical CVD at HbA1c of 44.5 mmol/mol (pre-diabetes). Ingenuity pathway analysis documented miR-18a-5p inhibiting mRNA expression of insulin-like growth factor-1, estrogen receptor-1, hypoxia-inducible factor-1α cellular communication network factor-2, and protein inhibitor of activated STAT 3, whilst metformin upregulated these mRNAs via transforming growth factor beta-1 and VEGF. We confirmed the pro-atherogenic effect of miR-18a-5p in subclinical CVD and identified several target genes for future CVD therapies.
