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SARS-CoV-2 Spike Protein Exacerbates Endothelial Dysfunction and Promotes Lung Injury in Aging Type 2 Diabetes
Nur Fatin Zalikha Zailan1, Hui Yee Chee2, Eusni Rahayu Mohd Tohit1
1Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.
Journal of Applied Toxicology : JAT
|August 4, 2026
Summary
Severe COVID-19 is worsened by diabetes-associated endothelial dysfunction (ED) and SARS-CoV-2 spike protein (SP). This interaction increases inflammation and lung injury, suggesting new therapeutic targets for high-risk patients.
Area of Science:
- Cardiovascular Biology
- Infectious Diseases
- Endocrinology
Background:
- Advanced age and diabetes mellitus (DM) are key risk factors for severe COVID-19 outcomes, including acute respiratory distress syndrome (ARDS) and increased mortality.
- SARS-CoV-2 spike protein (SP) interaction with ACE2 may disrupt the renin-angiotensin system (RAS), leading to vascular dysfunction, particularly in individuals with pre-existing endothelial dysfunction (ED).
Purpose of the Study:
- To investigate the synergistic mechanisms by which SP exacerbates diabetes-associated ED and contributes to severe COVID-19 pathology.
- To identify potential biomarkers and therapeutic targets for managing severe COVID-19 in patients with type 2 diabetes mellitus (T2DM).
Main Methods:
- Utilized an in vitro co-culture model of human aortic endothelial cells (HAoECs) and ACE2-transfected human bronchial epithelial cells (BEAS-2BACE2-eGFP).
- Stimulated HAoECs with serum from healthy adults and T2DM patients, with or without SP, to assess ED markers (ROS, ICAM-1, VCM-1, permeability).
- Measured ACE2 expression and Ang II levels in BEAS-2BACE2-eGFP cells and evaluated lung injury and cytokine release in the co-culture system.
Main Results:
- T2DM serum significantly increased oxidative stress, adhesion molecule expression, and endothelial permeability in HAoECs.
- Co-exposure to T2DM serum and SP markedly reduced ACE2 expression and elevated Ang II levels in BEAS-2BACE2-eGFP cells.
- Combined T2DM serum and SP treatment exacerbated endothelial dysfunction, heightened inflammation, induced lung epithelial injury, and increased pro-inflammatory cytokine release.
Conclusions:
- Diabetes-associated ED synergizes with SARS-CoV-2 SP to aggravate vascular inflammation and lung injury, contributing to severe COVID-19.
- Adhesion molecules and pro-inflammatory cytokines are potential biomarkers for severe COVID-19 in T2DM patients.
- RAS dysregulation and endothelial activation represent promising therapeutic targets for severe COVID-19 in the context of T2DM.
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