Inhibition of Protein Tyrosine Phosphatase Improves Angiogenesis via Enhancing Ang-1Tie-2 Signaling in Diabetes

Abstract EN

Diabetes is associated with impairment of angiogenesis such as reduction of myocardial capillary formation.

Our previous studies demonstrate that disruption of Angiopoietin-1 (Ang-1)/Tie-2 signaling pathway contributes to the diabetes-associated impairment of angiogenesis.

Protein tyrosine phosphatase (PTP) has a critical role in the regulation of insulin signal by inhibition of tyrosine kinase phosphorylation.

In present study, we examined the role of protein tyrosine phosphatase-1 (SHP-1) in diabetes-associated impairment of Ang-1/Tie-2 angiogenic signaling and angiogenesis.

SHP-1 expression was significantly increased in diabetic db/db mouse hearts.

Furthermore, SHP-1 bond to Tie-2 receptor and stimulation with Ang-1 led to SHP-1 dissociation from Tie-2 in mouse heart microvascular endothelial cell (MHMEC).

Exposure of MHMEC to high glucose (HG, 30 mmol/L) increased SHP-1/Tie-2 association accompanied by a significant reduction of Tie-2 phosphorylation.

Exposure of MHMEC to HG also blunted Ang-1-mediated SHP-1/Tie-2 dissociation.

Knockdown of SHP-1 significantly attenuated HG-induced caspase-3 activation and apoptosis in MHMEC.

Treatment with PTP inhibitors restored Ang-1-induced Akt/eNOS phosphorylation and angiogenesis.

Our data implicate a critical role of SHP-1 in diabetes-associated vascular complications, and that upregulation of Ang-1/Tie-2 signaling by targeting SHP-1 should be considered as a new therapeutic strategy for the treatment of diabetes-associated impairment of angiogenesis.