Mesenchymal stem cells ameliorate hyperglycemia-induced endothelial injury through modulation of mitophagy

Abstract

Mitochondrial dysfunction and excessive mitochondrial reactive oxygen species (ROS) are fundamental contributors to endothelial injury in diabetic states. Mesenchymal stem cells (MSCs) have exhibited an extraordinary cytoprotective effect that extends to the modulation of mitochondrial homeostasis. However, the underlying mechanisms have not been clearly defined. Emerging evidence has suggested that mitophagy could counteract mitochondrial-derived oxidative stress through the selective elimination of impaired or dysfunctional mitochondria. Therefore, we investigated whether MSCs could ameliorate high-glucose-induced endothelial injury through the modulation of mitophagy. We observed that exposure of human umbilical vein endothelial cells (HUVECs) to high glucose triggers mitochondrial impairment with excessive mitochondrial fragmentation and ROS generation, loss of membrane potential and reduced ATP production. Furthermore, mitophagy was blunted upon high glucose insult, which accelerated dysfunctional mitochondrial accumulation, initiating the mitochondrial apoptotic pathway and, eventually, endothelial dysfunction. MSCs treatment notably attenuated these perturbations accompanied by an enhancement of Pink1 and Parkin expression, whereas these beneficial effects of MSCs were abolished when either Pink1 or Parkin was knocked down. In aortas of diabetic rats, defective mitophagy was observed, which coincided with marked mitochondrial dysfunction. Ultrastructurally, RAECs from diabetic rats revealed a significant reduction in autophagic vacuoles and a marked increase in fragmented mitochondria. Importantly, the infusion of MSCs restored Pink1/Parkin-mediated mitophagy, ameliorated mitochondrial dysfunction and attenuated apoptosis in endothelial cells in diabetic rats. These results suggest that MSCs may protect endothelial cells from hyperglycemia-induced injury by ameliorating mitochondrial dysfunction via Pink1/Parkin –mediated mitophagy

Protective effects of metformin against osteoarthritis through upregulation of SIRT3-mediated PINK1/Parkin-dependent mitophagy in primary chondrocytes

“…We also demonstrated that metformin activated SIRT3/PINK1/Parkin pathway could reverse the increased ROS level and loss of ΔѰM. Consistent with our results, studies have also shown that Parkin-mediated mitophagy may eliminate damaged mitochondria and decrease the level of ROS in human umbilical vein endothelial cells and fibroblasts (24,25).…”

Mesenchymal Stem Cells Attenuate Diabetic Lung Fibrosis via Adjusting Sirt3-Mediated Stress Responses in Rats

“…MSCs are found to ameliorate various diabetic complications, such as diabetic cardiomyopathy, retinopathy, nephropathy, peripheral neuropathy, and foot ulcer [33][34][35][36][37]. In our previous works, we also found that MSCs ameliorate hyperglycemia-induced endothelial injury [38,39] and diabetic kidney injury [40]. However, there are few papers that have reported the effects and potential mechanisms of MSCs on Sirt3 and diabetic lung injury.…”

“…To generate bone marrow MSCs, bone marrow mononuclear cells were harvested by flushing the tibiae and femurs of 3-week-old male Sprague-Dawley rats (50-55 g body weight) with phosphate-buffered solution (PBS). Bone marrow MSCs were cultured in complete medium (90% Dulbecco's modified Eagle's medium-low glucose+10% fetal bovine serum) (HyClone, Logan, USA) and grown with 5% CO 2 in a humidified atmosphere at 37°C, identified as described previously [39]. Bone marrow MSCs were passaged every 2 to 3 days and were used for transplantation at passage three or four.…”

Astragaloside IV prevents high glucose‑induced cell apoptosis and inflammatory reactions through inhibition of the JNK pathway in human umbilical vein endothelial cells

“…The increase of endothelial cell apoptosis is one of the primary characteristics of endothelial dysfunction (4) and one of the most important effects on HUVECs in high glucose conditions (46). The present data indicated that high glucose conditions induced cell apoptosis.…”