Elevated expression of mechanosensory polycystins in human carotid atherosclerotic plaques: association with p53 activation and disease severity.

Aimilia Varela,Efthimia K Basdra,Athanasios G Papavassiliou,Christos Manopoulos,Sokrates Tsangaris,Fragiska Sigala,Maria-Anastasia Andri,Christina Piperi,George Agrogiannis,Constantinos H Davos

doi:10.1038/srep13461

Abstract

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.

Highlights

Form a mechanosensor complex that is important for cilia movement as well as for the development of kidney, skeletal muscle and heart
Using an in vitro cell culture model, we investigated the acute effects of oscillatory shear stress on polycystin 1 (PC-1) and -2 expression
The present study investigates for the first time the implication of the mechanosensitive molecules PC-1 and polycystin 2 (PC-2) in the induction of atherosclerosis and plaque formation

Summary

Introduction

Form a mechanosensor complex that is important for cilia movement as well as for the development of kidney, skeletal muscle and heart. PCs have been found localized in several cell types including osteoblasts, cardiac myocytes and endothelial cells acting primarily as transmembrane mechanotransduction molecules that regulate cellular function, proliferation and apoptosis[5,6,7,8,9,10,11,12,13,14,15]. There is evidence that a downstream target of PC-1 signalling is the tumour suppressor protein p53, a critical regulator of cell proliferation and apoptosis. It has been suggested that PC-1 and p53 participate in an autofeedback pathway which functions to tightly regulate their expression, and aberrant expression of either protein leads to impaired development[28,29]. Biomechanical stress has been found to induce p53 activation in SMCs, leading to apoptosis via p38 mitogen-activated protein kinase (MAPK) signalling[31,32]

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Results

Conclusion