Elevated expression of mechanosensory polycystins in human carotid atherosclerotic plaques: association with p53 activation and disease severity.
Atherosclerotic plaque formation is associated with irregular distribution of wall shear stress (WSS) that modulates endothelial function and integrity. Polycystins (PC)-1/-2 constitute a flow-sensing protein complex in endothelial cells, able to respond to WSS and induce cell-proliferation changes leading to atherosclerosis. An endothelial cell-culture system of measurable WSS was established to detect alterations in PCs expression under conditions of low- and high-oscillatory shear stress in vitro. PCs expression and p53 activation as a regulator of cell proliferation were further evaluated in vivo and in 69 advanced human carotid atherosclerotic plaques (AAPs). Increased PC-1/PC-2 expression was observed at 30-60 min of low shear stress (LSS) in endothelial cells. Elevated PC-1 expression at LSS was followed by p53 potentiation. PCs immunoreactivity localizes in areas with macrophage infiltration and neovascularization. PC-1 mRNA and protein levels were significantly higher than PC-2 in stable fibroatherotic (V) and unstable/complicated (VI) AAPs. Elevated PC-1 immunostaining was detected in AAPs from patients with diabetes mellitus, dyslipidemia, hypertension and carotid stenosis, at both arteries (50%) or in one artery (90%). PCs seem to participate in plaque formation and progression. Since PC-1 upregulation coincides with p38 and p53 activation, a potential interplay of these molecules in atherosclerosis induction is posed.
1] Department of Biological Chemistry, University of Athens Medical School, Athens 11527, Greece [2] Cardiovascular Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
Aimilia
A
Varela
Department of Biological Chemistry, University of Athens Medical School, Athens 11527, Greece.
Christina
C
Piperi
Vascular Surgery Division, First Department of Propaedeutic Surgery, 'Hippokrateion' General Hospital, University of Athens Medical School, Athens 11527, Greece.
Fragiska
F
Sigala
First Department of Pathology, 'Laikon' General Hospital, University of Athens Medical School, Athens 11527, Greece.
George
G
Agrogiannis
Cardiovascular Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
Constantinos H
CH
Davos
Laboratory of Biofluid Mechanics and Biomedical Engineering, School of Mechanical Engineering, National Technical University of Athens, Athens 15780, Greece.
Maria-Anastasia
MA
Andri
Laboratory of Biofluid Mechanics and Biomedical Engineering, School of Mechanical Engineering, National Technical University of Athens, Athens 15780, Greece.
Christos
C
Manopoulos
Laboratory of Biofluid Mechanics and Biomedical Engineering, School of Mechanical Engineering, National Technical University of Athens, Athens 15780, Greece.
Sokrates
S
Tsangaris
Department of Biological Chemistry, University of Athens Medical School, Athens 11527, Greece.
Efthimia K
EK
Basdra
Department of Biological Chemistry, University of Athens Medical School, Athens 11527, Greece.
Athanasios G
AG
Papavassiliou
D002339:Carotid Arteries / Q000473:pathology*; D004730:Endothelium, Vascular / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D040542:Mechanotransduction, Cellular; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012307:Risk Factors; D012720:Severity of Illness Index; D013314:Stress, Mechanical; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D050396:TRPP Cation Channels; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases