Activation of protein kinase C and disruption of endothelial monolayer integrity by sodium arsenite—Potential mechanism in the development of atherosclerosis

Abstract

Arsenic exposure has been shown to exacerbate atherosclerosis, beginning with activation of the endothelium that lines the vessel wall. Endothelial barrier integrity is maintained by proteins of the adherens junction (AJ) such as vascular endothelial cadherin (VE-cadherin) and β-catenin and their association with the actin cytoskeleton. In the present study, human aortic endothelial cells (HAECs) were exposed to 1, 5 and 10 μM sodium arsenite [As(III)] for 1, 6, 12 and 24 h, and the effects on endothelial barrier integrity were determined. Immunofluorescence studies revealed formation of actin stress fibers and non-uniform VE-cadherin and β-catenin staining at cell-cell junctions that were concentration and time-dependent. Intercellular gaps were observed with a measured increase in endothelial permeability. In addition, concentration-dependent increases in tyrosine phosphorylation (PY) of β-catenin and activation of protein kinase Cα (PKCα) were observed. Inhibition of PKCα restored VE-cadherin and β-catenin staining at cell-cell junctions and abolished the As(III) induced formation of actin stress fibers and intercellular gaps. Endothelial permeability and PY of β-catenin were also reduced to basal levels. These results demonstrate that As(III) induces activation of PKCα, which leads to increased PY of β-catenin downstream of PKCα activation. Phosphorylation of β-catenin plausibly severs the association of VE-cadherin and β-catenin, which along with formation of actin stress fibers, results in intercellular gap formation and increased endothelial permeability. To the best of our knowledge, this is the first report demonstrating that As(III) causes a loss of endothelial monolayer integrity, which potentially could contribute to the development of atherosclerosis.

Mechanism of the protective effects of the combined treatment with rhynchophylla total alkaloids and sinapine thiocyanate against a prothrombotic state caused by vascular endothelial cell inflammatory damage

“…In turn, this triggers Ca 2+ release from the endoplasmic reticulum, resulting in an increased concentration of cytosolic Ca 2+ and further activation of PKC (24,25). PKC is one of the most important molecules involved in post-membrane signaling transduction and participates in a crucial cell-signaling transduction pathway for atherosclerosis (26). .05 vs. TNF-α group.…”

Protective effect of pretreatment with cilostazol on cytotoxicity of cadmium and arsenite in cultured vascular endothelial cells

“…Vascular endothelial cells also have been suspected as primary targets in the process of inorganic arsenic-induced vascular diseases (Engle et al, 1994). A recent study has demonstrated that iAs III causes a loss of endothelial monolayer integrity (Pereira et al, 2007). Since vascular endothelial cell damage is an important event in the pathogenesis of atherosclerosis (Munro and Cotran, 1988;Ross, 1993), protection of the pathologic changes in vascular endothelial cells could contribute to the prevention of atherosclerosis.…”

Arsenic in Drinking Water and Stroke Hospitalizations in Michigan

“…Direct and indirect effects of arsenic exposure on ischemic stroke risk are biologically plausible further supporting the hypothesis that arsenic is associated with stroke. Arsenic may directly accelerate atherosclerosis by inducing endothelial dysfunction because arsenic disrupts endothelial monolayer integrity, 10 increases production of reactive oxygen 28 and nitrogen 29 species contributing to cytotoxicity, increases inflammatory markers, 29 and disrupts the intravascular matrix. 7 Arsenic may also increase stroke risk through platelet-mediated effects because arsenic increases platelet aggregation and the formation of arterial thrombi.…”

“…6 At concentrations Ͼ300 g/L, health risks from arsenic are unequivocal; however, evaluating risks from chronic, low-level exposures (Ͻ100 g/L) has generated much debate. 7 Mechanistic and human studies have suggested a role for arsenic in atherosclerosis, 8 -11 perhaps through decreases in the vascular matrix, 8 disruption of endothelial integrity, 10 and enhanced platelet aggregation. 9 Roughly 85% of strokes in the United States are ischemic in nature with the primary underlying condition being atherosclerosis.…”