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Detrimental interactions of hypoxia and complement MASP-1 in endothelial cells as a model for atherosclerosis-related
Flóra Demeter1, Zsuzsanna Németh1, Erika Kajdácsi1,2
1Research Laboratory, Department of Internal Medicine and Haematology, Semmelweis University, Szentkirályi U. 46, Budapest, 1088, Hungary.
Insights
Hypoxia potentiates mannose-binding lectin-associated serine protease-1 (MASP-1) effects on endothelial cells, exacerbating atherosclerosis-related diseases like stroke and acute myocardial infarction (AMI). MASP-1 emerges as a potential therapeutic target.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cellular Physiology
Background:
- Hypoxia and the complement lectin pathway (CLP) are implicated in atherosclerosis, stroke, and acute myocardial infarction (AMI).
- Mannose-binding lectin-associated serine protease-1 (MASP-1), a key CLP enzyme, promotes endothelial cell (EC) inflammation via protease-activated receptors (PARs).
Purpose of the Study:
- To investigate the interaction between hypoxia and MASP-1 in endothelial cells (ECs) within the context of atherosclerosis-related diseases.
- To elucidate the molecular mechanisms underlying the combined effects of hypoxia and MASP-1 on ECs.
Main Methods:
- Endothelial cells (ECs) were exposed to hypoxia and/or MASP-1 treatment.
- Assessed EC functions including wound healing, gene/protein expression (ICAM-1, ICAM-2, PAR2, E-selectin, VCAM-1), cytokine production (GROα, IL-8), endothelial permeability, and intracellular signaling pathways (Ca2+, CREB, NFκB).
Main Results:
- Hypoxia impaired EC wound healing, altered ICAM-1/ICAM-2 expression, and upregulated PAR2. Both hypoxia and MASP-1 increased GROα, IL-8, and endothelial permeability.
- Hypoxia and MASP-1 cooperatively disrupted vascular network integrity and activated Ca2+, CREB, and NFκB pathways.
- Co-treatment upregulated E-selectin expression, a key molecule in neutrophil homing, while VCAM-1 remained unaffected.
Conclusions:
- Hypoxia potentiates MASP-1 effects on ECs, partly via increased PAR expression, leading to synergistic disruption of vascular integrity and inflammatory signaling.
- These interactions exacerbate the progression of atherosclerosis-related stroke and AMI.
- MASP-1 represents a promising therapeutic target for managing acute phases of atherosclerosis-related cardiovascular events.
Abstract:
Both hypoxia and the complement lectin pathway (CLP) are involved in atherosclerosis and atherosclerosis-related stroke and acute myocardial infarction (AMI). We have previously shown that mannose-binding lectin-associated serine protease-1 (MASP-1), the most abundant enzyme of CLP, induces an inflammatory phenotype of endothelial cells (ECs) by cleaving protease activated receptors (PARs). In the absence of data, we aimed to investigate whether hypoxia and MASP-1 interact at the level of ECs, to better understand their role in atherosclerosis-related diseases. Hypoxia attenuated the wound healing ability of ECs, increased ICAM-1 and decreased ICAM-2 expression and upregulated PAR2 gene expression. Hypoxia and MASP-1 increased GROα and IL-8 production, and endothelial permeability without potentiating each other's effects, whereas they cooperatively disrupted vascular network integrity, activated the Ca2+, CREB and NFκB signaling pathways, and upregulated the expression of E-selectin, a crucial adhesion molecule in neutrophil homing. VCAM-1 expression was not influenced either by hypoxia, or by MASP-1. In summary, hypoxia potentiates the effect of MASP-1 on ECs, at least partially by increasing PAR expression, resulting in interaction at several levels, which may altogether exacerbate stroke and AMI progression. Our findings suggest that MASP-1 is a potential drug target in the acute phase of atherosclerosis-related diseases.
