Sitagliptin-mediated preservation of endothelial progenitor cell function via augmenting autophagy enhances ischaemic angiogenesis in diabetes.
Xiaozhen DaiJun ZengXiaoqing YanQian LinKai WangJing ChenFeixia ShenXuemei GuYuehui WangJun ChenKejian PanLu CaiKupper A WintergerstYi TanPublished in: Journal of cellular and molecular medicine (2017)
Recently, the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin, a major anti-hyperglycaemic agent, has received substantial attention as a therapeutic target for cardiovascular diseases via enhancing the number of circulating endothelial progenitor cells (EPCs). However, the direct effects of sitagliptin on EPC function remain elusive. In this study, we evaluated the proangiogenic effects of sitagliptin on a diabetic hind limb ischaemia (HLI) model in vivo and on EPC culture in vitro. Treatment of db/db mice with sitagliptin (Januvia) after HLI surgery efficiently enhanced ischaemic angiogenesis and blood perfusion, which was accompanied by significant increases in circulating EPC numbers. EPCs derived from the bone marrow of normal mice were treated with high glucose to mimic diabetic hyperglycaemia. We found that high glucose treatment induced EPC apoptosis and tube formation impairment, which were significantly prevented by sitagliptin pretreatment. A mechanistic study found that high glucose treatment of EPCs induced dramatic increases in oxidative stress and apoptosis; pretreatment of EPCs with sitagliptin significantly attenuated high glucose-induced apoptosis, tube formation impairment and oxidative stress. Furthermore, we found that sitagliptin restored the basal autophagy of EPCs that was impaired by high glucose via activating the AMP-activated protein kinase/unc-51-like autophagy activating kinase 1 signalling pathway, although an autophagy inhibitor abolished the protective effects of sitagliptin on EPCs. Altogether, the results indicate that sitagliptin-induced preservation of EPC angiogenic function results in an improvement of diabetic ischaemia angiogenesis and blood perfusion, which are most likely mediated by sitagliptin-induced prevention of EPC apoptosis via augmenting autophagy.
Keyphrases
- high glucose
- endothelial cells
- oxidative stress
- endoplasmic reticulum stress
- induced apoptosis
- cell death
- signaling pathway
- type diabetes
- diabetic rats
- vascular endothelial growth factor
- bone marrow
- protein kinase
- cardiovascular disease
- dna damage
- wound healing
- ischemia reperfusion injury
- mesenchymal stem cells
- computed tomography
- contrast enhanced
- magnetic resonance imaging
- adipose tissue
- tyrosine kinase
- cell proliferation
- high fat diet induced
- pi k akt
- coronary artery bypass
- cardiovascular risk factors
- smoking cessation