Protein Tyrosine Phosphatase (PTP) 1B Inhibition Improves Endoplasmic Reticulum Stress-Induced Apoptosis and Impaired Angiogenic Response in Endothelial Cells

Abstract

Insulin is not only important for glucose homeostasis, but also plays a critical role in the activation of endothelial nitric oxide synthase (eNOS) to synthesize nitric oxide (NO) and keeping the endothelium functional. Conditions which result in insulin resistance, such as diabetes and obesity, cause impairment of endothelial function, a condition known as endothelial dysfunction that features a reduced release of NO. Protein tyrosine phosphatase (PTP) 1B, is a known negative regulator of insulin receptor, that has been implicated in the pathogenesis of insulin resistance and endothelial dysfunction. Owing to its critical location at the surface of the endoplasmic reticulum (ER), PTP1B has been found to play an important role in ER stress response. However, the role of ER stress in PTP1B-mediated endothelial dysfunction is not fully elucidated. Toa address this, ER stress was induced pharmacologically in endothelial cells using thapsigargin, in the presence or absence of either a small molecule inhibitor of PTP1B or silencing siRNA duplexes, followed by the assessment of the expression of key ER stress markers, angiogenic capacity and apoptotic signals. We report here, that PTP1B inhibition protected cells against ER stress and ER stress-induced impairment in eNOS activation and angiogenic capacity. PTP1B inhibition or silencing also protected against ER stress-induced endothelial cell apoptosis. Moreover, PTP1B blockade also suppressed ER stress-activated autophagy. Our data emphasize on the critical role of PTP1B in ER stress-mediated endothelial cell dysfunction and highlights the therapeutic potential of PTP1B inhibition against ER stress-mediated cell death and impairment of endothelial function to prevent cardiovascular disease in pathologies charactereized by the activation of ER stress such as diabetes.