Nemzeti Gyógyszerkutatási és Fejlesztési Laboratórium (PharmaLab)(RRF-2.3.1-21-2022-00015)
Támogató: NKFIH
Piacvezérelt kutatás-fejlesztési és innovációs projektek támogatása(2020-1.1.2-PIACI-KFI-2021-00273)
Támogató: Nemzeti Kutatási, Fejlesztési és Innovációs Hivatal
(Open access funding provided by Semmelweis University)
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.
