T‐cadherin protects endothelial cells from oxidative stress‐induced apoptosis

Abstract

In vascular tissue, T-cadherin (T-cad) is up-regulated in vivo under disease conditions associated with oxidative stress and concomitant cell migration, proliferation and apoptosis/survival. Using cultures of human umbilical vein endothelial cells (HUVEC), we examined whether there is a functional relationship between oxidative stress, T-cad expression, and cell survival status. Culture of HUVEC under conditions of oxidative stress (e.g., serum deprivation, inclusion of H2O2) resulted in increased T-cad expression. Oxidative stress-induced increases in T-cad were inhibited by the free radical-scavenging antioxidant, N-acetylcysteine, and the flavin-containing oxidase inhibitor, diphenyleneiodonium. Thus reactive oxygen species (ROS) contribute to stress-induced elevation of T-cad in HUVEC. Compared with control cells, HUVEC overexpressing T-cad (T-cad+-HUVEC) had higher phosphorylation levels for phosphatidylinositol 3-kinase (PI3K) target Akt and mTOR target p70(S6K) (survival pathway regulators), but lower levels for p38MAPK (death pathway regulator). T-cad+-HUVEC exposed to stress (serum-deprivation, TNF-alpha, actinomycin D, staurosporine) exhibited reduced caspase activation together with increased cell survival. Protection against stress-induced apoptosis in T-cad+-HUVEC was abrogated by either PI3K-inhibitor wortmannin or mTOR-inhibitor rapamycin. We conclude that T-cad overexpression in HUVEC protects against stress-induced apoptosis through activation of the PI3K/Akt/mTOR survival signal pathway and concomitant suppression of the p38 MAPK proapoptotic pathway. ROS-induced changes in T-cad expression may play an important role in controlling tissue cellularity during vascular remodeling.

Malignant Transformation in Skin is Associated with the Loss of T-Cadherin Expression in Human Keratinocytes and Heterogeneity in T-Cadherin Expression in Tumor Vasculature

“…By using dominant negative and constitutively active forms of Rho, Rac and Cdc42 it was shown that Rho GTPases act downstream of T-cadherin and the activation of Rac1 and Cdc42 GTPases results in increased phosphorylation of LIMK1 kinase, actin and microtubule cytoskeleton rearrangements, activation of endothelial cell migration and increased permeability of endothelial cell monolayer Semina et al, 2009). Overexpression of T-cadherin in endothelial cells led to higher phosphorylation levels for phosphatidylinositol-3-kinase (PI3K) target Akt and mTOR target p70 S6K involved in survival pathway in endothelial cells, but lower levels for p38MAPK (death pathway) (Joshi et al, 2005). In line with that, it was shown that T-cadherin mediated activation of PI3K/Akt/GSK3β signaling which protects endothelial cells from oxidative stressinduced apoptosis (Joshi et al, 2005).…”

The role of leptin/adiponectin ratio in metabolic syndrome and diabetes

“…The activation of AdipoR1 and R2 results in increased hepatic and skeletal muscle fatty acid oxidation, increased skeletal muscle lactate production, reduced hepatic gluconeogenesis, increased cellular glucose uptake, and inhibition of inflammation and oxidative stress [53]. In vascular endothelial cells, activation of T-cadherin is protective against oxidative stress-induced apoptosis [54]. Several mechanisms have been suggested to explain the anti-inflammatory effects of adiponectin, including direct actions on inflammatory cells, actions on NF-κB, and interactions with TNF-α [52].…”

Insights into the Low Adhesive Capacity of Human T-cadherin from the NMR Structure of Its N-terminal Extracellular Domain

“…Based on these observations, it has been suggested that T-cadherin functions as a signaling molecule involved e.g. in angiogenesis, cell growth, proliferation, migration, and survival (8,13,14). T-cadherin is a receptor for the hexameric and higher oligomeric forms of adiponectin/Acrp30 (15) and for low-density lipoproteins (LDL) (13, 16).…”

“…T-cadherin is a receptor for the hexameric and higher oligomeric forms of adiponectin/Acrp30 (15) and for low-density lipoproteins (LDL) (13, 16). Moreover, it has been shown to influence signaling via the RhoA/ROCK, Rac, Erk1/2, and PI3K/Akt/mTOR pathways (8,13,17).Cell-cell adhesion mediated by classical cadherins is induced by the presence of calcium. Current models (18 -20) of this process postulate an initial oligomerization at the cell surface (cis) followed by the formation of the adhesive contact via intercellular cadherin dimers (trans).…”

“…T-cadherin is a receptor for the hexameric and higher oligomeric forms of adiponectin/Acrp30 (15) and for low-density lipoproteins (LDL) (13, 16). Moreover, it has been shown to influence signaling via the RhoA/ROCK, Rac, Erk1/2, and PI3K/Akt/mTOR pathways (8,13,17).…”