High glucose and free fatty acids induce endothelial progenitor cell senescence via PGC‐1α/SIRT1 signaling pathway

Abstract

The objective of the research was to investigate the function of endothelial progenitor cells (EPCs) in the conditions of high glucose and lipids, which has been widely used to mimic the metabolic disorder that occurs in type 2 diabetic mellitus, and further to verify the role of PGC-1α and SIRT1, cellular energy metabolism regulators, in the process of senescence of EPCs with these combined stimuli. Circulating EPCs were incubated in absence or presence of high glucose (25 mM), FFA (200 µM) or both. EPCs senescence was assessed by β-galactosidase staining, EPCs telomerase activity was measured by telomeric repeat ampli-fication protocol assay, in vitro angiogenesis assay and MTT assays were performed to assess angiogenesis and proliferation ability of EPCs. The results showed that combined stimuli inhibited EPCs reendothelialization ability in vitro, accelerated EPCs senescence and decreased the telomerase activity. Meanwhile, with combined stimuli, the expression of PGC-1α increased whereas SIRT1 expression decreased in EPCs accompanied by activation of P53/P21 signaling pathway. Conversely, transfection of EPCs with PGC-1α-siRNA rescued EPCs premature senescence and up-regulated SIRT1 and decreased P53/P21 expression, correlating closely with the down-regulation of PGC-1α itself. In addition, the combined stimuli induced up-regulation of PGC-1α expression was partly mediated by ROS and P38 signaling pathway. Overall, the data presented here identify PGC-1α as a potent negative regulator of EPCs' senescence under combined stimuli, which is partly mediated by SIRT1/P53/P21 signaling pathway.

Resveratrol attenuates type 2 diabetes mellitus by mediating mitochondrial biogenesis and lipid metabolism via Sirtuin type 1

“…Furthermore, the results of an in vivo study indicated that RSV increases SIRT1 expression and stimulates PGC-1a activity in skeletal muscle (24). The results of the present study demonstrate that RSV is able to mitigate the STZ-induced inhibition of SIRT1, PGC-1α and FOXO3a, which is in accordance with previous results (25)(26)(27). A number of previous studies have reported that INS resistance is associated with mitochondrial dysfunction (22) and these results may be caused by oxidative stress (28).…”

LncRNA‐ES3 inhibition by Bhlhe40 is involved in high glucose–induced calcification/senescence of vascular smooth muscle cells

“…2 There are complex pathways involved in the mechanisms of vascular calcification/aging in diabetes, including HG regulation in both endothelial and VSMC layers. 3,4,7,19 Vascular endothelial dysfunction is associated with diabetic conditions, 6,7,20 while little is known about the mechanisms driving calcification/senescence of VSMCs under diabetic conditions.…”

“…3,4 The mechanisms underlying vascular calcification/aging in diabetes are complex and multifactorial and include high glucose (HG) regulation at the endothelial level. [5][6][7] However, few findings have been reported supporting the hypothesis that HG alters calcification/senescence of vascular smooth muscle cells (VSMCs).…”

lncRNA-ES3/miR-34c-5p/BMF axis is involved in regulating high-glucose-induced calcification/senescence of VSMCs

“…Furthermore, diabetic artery calcification/aging leads to arteriosclerosis, amputations, kidney failure, stroke, and increased incidence of cardiovascular events and mortality [3, 4]. Hyperglycemia is the main characteristic of diabetes and increasing evidence has demonstrated that high glucose is an important regulator of endothelial cell senescence, wherein accumulative premature senescent cells participate in the onset and progress of diabetic vascular aging [5, 6]. However, very few reports have studied the effect of high glucose on calcification/senescence of vascular smooth muscle cells (VSMCs).…”