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The Specific Molecular Changes Induced by Diabetic Conditions in Valvular Endothelial Cells and upon Their
Monica Madalina Tucureanu1, Letitia Ciortan1, Razvan Daniel Macarie1
1Biopathology and Therapy of Inflammation, Institute of Cellular Biology and Pathology "Nicolae Simionescu", 050568 Bucharest, Romania.
Insights
High glucose damages aortic valve cells by altering their structure and interactions with monocytes, contributing to aortic valve disease in diabetes. This research reveals new molecular pathways for potential therapeutic strategies.
Area of Science:
- Cardiovascular Biology
- Endothelial Cell Biology
- Diabetes Research
Background:
- Aortic valve disease (AVD) is a global health issue.
- Diabetes accelerates AVD progression, but mechanisms are unclear.
- Valvular endothelial cell (VEC) dysfunction and monocyte crosstalk are implicated.
Purpose of the Study:
- Identify molecular changes in VECs under high glucose (HG).
- Investigate VEC-monocyte interactions in normal (NG) and HG conditions.
- Elucidate novel mechanisms of diabetic valvular dysfunction.
Main Methods:
- Cultured VECs and THP-1 monocytes in NG/HG.
- Performed RNAseq for transcriptomic analysis.
- Validated key molecules using qPCR, Western blot, and immunofluorescence.
Main Results:
- HG induced transcriptomic changes in VECs affecting cytoskeleton, focal adhesions, and cell junctions.
- Altered VEC structure impaired endothelial function, increasing permeability.
- VEC dysfunction enhanced monocyte adhesion and transmigration.
Conclusions:
- Discovered molecular mechanisms of VEC dysfunction in diabetes.
- Findings link HG-induced VEC changes and monocyte interactions to valvular dysfunction.
- Provides insights for novel therapeutic strategies in AVD.
Abstract:
Aortic valve disease (AVD) represents a global public health challenge. Research indicates a higher prevalence of diabetes in AVD patients, accelerating disease advancement. Although the specific mechanisms linking diabetes to valve dysfunction remain unclear, alterations of valvular endothelial cells (VECs) homeostasis due to high glucose (HG) or their crosstalk with monocytes play pivotal roles. The aim of this study was to determine the molecular signatures of VECs in HG and upon their interaction with monocytes in normal (NG) or high glucose conditions and to propose novel mechanisms underlying valvular dysfunction in diabetes. VECs and THP-1 monocytes cultured in NG/HG conditions were used. The RNAseq analysis revealed transcriptomic changes in VECs, in processes related to cytoskeleton regulation, focal adhesions, cellular junctions, and cell adhesion. Key molecules were validated by qPCR, Western blot, and immunofluorescence assays. The alterations in cytoskeleton and intercellular junctions impacted VEC function, leading to changes in VECs adherence to extracellular matrix, endothelial permeability, monocyte adhesion, and transmigration. The findings uncover new molecular mechanisms of VEC dysfunction in HG conditions and upon their interaction with monocytes in NG/HG conditions and may help to understand mechanisms of valvular dysfunction in diabetes and to develop novel therapeutic strategies in AVD.
