scholarly journals The Role of Protein Tyrosine Phosphatase (PTP)-1B in Cardiovascular Disease and Its Interplay with Insulin Resistance

Biomolecules ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. 286 ◽  
Author(s):  
Abdelsalam ◽  
Korashy ◽  
Zeidan ◽  
Agouni
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Endothelial Dysfunction ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Negative Regulator ◽  
Cardiovascular Disorders ◽  
Protein Tyrosine ◽  
Obesity And Diabetes ◽  
Ptp 1B

Endothelial dysfunction is a key feature of cardiovascular disorders associated with obesity and diabetes. Several studies identified protein tyrosine phosphatase (PTP)-1B, a member of the PTP superfamily, as a major negative regulator for insulin receptor signaling and a novel molecular player in endothelial dysfunction and cardiovascular disease. Unlike other anti-diabetic approaches, genetic deletion or pharmacological inhibition of PTP1B was found to improve glucose homeostasis and insulin signaling without causing lipid buildup in the liver, which represents an advantage over existing therapies. Furthermore, PTP1B was reported to contribute to cardiovascular disturbances, at various molecular levels, which places this enzyme as a unique single therapeutic target for both diabetes and cardiovascular disorders. Synthesizing selective small molecule inhibitors for PTP1B is faced with multiple challenges linked to its similarity of sequence with other PTPs; however, overcoming these challenges would pave the way for novel approaches to treat diabetes and its concurrent cardiovascular complications. In this review article, we summarized the major roles of PTP1B in cardiovascular disease with special emphasis on endothelial dysfunction and its interplay with insulin resistance. Furthermore, we discussed some of the major challenges hindering the synthesis of selective inhibitors for PTP1B.

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

2021 ◽  
Author(s):  
Shahenda Salaheldine Abdelsalam ◽  
Abdelali Agouni
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Critical Role ◽  
Ptp 1B

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.

scholarly journals Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR−/− mouse model of atherosclerosis

2017 ◽  
Vol 131 (20) ◽  
pp. 2489-2501 ◽  
Author(s):  
Dawn Thompson ◽  
Nicola Morrice ◽  
Louise Grant ◽  
 Samantha Le Sommer ◽  
Emma K. Lees ◽  
...  
Keyword(s):  
Mouse Model ◽  
Atherosclerotic Plaque ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Plaque Formation ◽  
Negative Regulator ◽  
Protein Tyrosine Phosphatase 1B ◽  
Cvd Risk ◽  
Protein Tyrosine ◽  
Atherosclerotic Plaque Formation

Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with type 1 or type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance, due to impaired insulin receptor (IR) signalling. Here, we demonstrate that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR prevents and reverses atherosclerotic plaque formation in an LDLR−/− mouse model of atherosclerosis. Acute (single dose) or chronic PTP1B inhibitor (trodusquemine) treatment of LDLR−/− mice decreased weight gain and adiposity, improved glucose homeostasis and attenuated atherosclerotic plaque formation. This was accompanied by a reduction in both, circulating total cholesterol and triglycerides, a decrease in aortic monocyte chemoattractant protein-1 (MCP-1) expression levels and hyperphosphorylation of aortic Akt/PKB and AMPKα. Our findings are the first to demonstrate that PTP1B inhibitors could be used in prevention and reversal of atherosclerosis development and reduction in CVD risk.

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