Sitagliptin Reduces Endothelial Dysfunction and Apoptosis Induced by High-Fat Diet and Palmitate in Thoracic Aortas and Endothelial Cells via ROS-ER Stress-CHOP Pathway

Abstract

Macrovascular disease is tightly associated with obesity-induced metabolic syndrome. Sitagliptin (SIT), an orally stable selective inhibitor of Dipeptidyl peptidase-4 (DPP-4), has protective effects on endothelium. However, the mechanisms enabling SIT to exhibit resistance to diet-induced obesity (DIO) related with reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress in the aorta and endothelial cells have not been reported yet. Therefore, the present study was conducted to determine if SIT exerts protective role in the thoracic aortas isolated from the high-fat diet (HFD)-treated rats and palmitate (PA)-treated endothelial cells by alleviating ROS and ER stress. Male Sprague Dawley rats were randomly divided into standard chow diet (SCD), HFD and HFD plus sitagliptin administration (HFD + SIT) groups. The rats of latter two groups were given HFD fodder for 12 weeks, then the HFD + SIT rats were treated with SIT (10 mg/kg/d) by intragastric administration for another 8 weeks. The body mass, vascular tension, serum oxidative stress indices and inflammatory parameters, pathological changes, protein expression of endothelial nitric oxide synthase (eNOS), the genes associated with ER stress and apoptosis in the thoracic aorta were measured. Furthermore, cell proliferation, ROS and the protein expression associated with ER stress (especially CHOP) and apoptosis were assessed in human umbilical vein endothelial cells (HUVECs) incubated with SIT and PA. Compared to the SCD rats, the HFD rats had higher serum lipid levels, decreased vascular tension, increased inflammation, oxidative and ER stress, and apoptosis of endothelial cells. PA promoted ROS generation, ER stress and apoptosis, inhibited cell proliferation in HUVECs. SIT treatment obviously ameliorated apoptosis via alleviating ROS and ER stress in the thoracic aortas isolated from HFD-fed rats and PA-treated HUVECs. The results suggest that SIT improved endothelial function via promoting cell proliferation and alleviating ROS-ER stress-CHOP pathway both in vivo and in vitro.

Exploring Promising Therapies for Non-Alcoholic Fatty Liver Disease: A ClinicalTrials.gov Analysis

“… 87 The drug works by reducing cell death in liver cells, decreasing fat production in the liver, and managing oxidative stress and related inflammation. 88 In one clinical trial, researchers explored the effectiveness of combining sitagliptin with insulin glargine for treating NAFLD in T2DM patients, comparing it to the combination of liraglutide and metformin.…”

“…DPP-4 inhibitors like Sitagliptin and SGLT2 inhibitors such as Tofogliflozin showcase the intertwined pathophysiology of NAFLD and T2DM, underscoring the potential benefits these antidiabetic agents might confer on hepatic steatosis and inflammation. 84 , 88 …”

“…79 DPP-4 inhibitors like Sitagliptin and SGLT2 inhibitors such as Tofogliflozin showcase the intertwined pathophysiology of NAFLD and T2DM, underscoring the potential benefits these antidiabetic agents might confer on hepatic steatosis and inflammation. 84,88 Moreover, traditional agents like UDCA and vitamins like Vitamin E and Vitamin D underscore the multifactorial therapeutic approach to NAFLD. While UDCA's hepatoprotective and anti-apoptotic properties offer therapeutic possibilities, Vitamin E's antioxidant prowess suggests potential therapeutic benefits.…”

Aldose Reductase (AR) Mediates and Perivascular Adipose Tissue (PVAT) Modulates Endothelial Dysfunction of Short-Term High-Fat Diet Feeding in Mice

“…Although the STZ model induces a Type I diabetes state of severe hyperglycemia, our HFD model increased blood glucose by approximately 20%, yet this may be sufficient to drive AR-dependent effects in the endothelium. A previous study showed that only 2 weeks of HFD feeding in young male C57BL/6J (WT) mice induced endothelial cell insulin resistance [44], perhaps due to increased circulating fatty acids such as palmitate [45]. How AR contributes to the earliest deleterious changes in endothelial cells that give rise to ED under HFD feeding remains both a mystery and a potential therapeutic target [15].…”

Paeonol Promotes Reendothelialization After Vascular Injury Through Activation of c-Myc/VEGFR2 Signaling Pathway

“…2 Endothelial dysfunction can be induced by vascular injury, such as stent implantation. Preexisting vascular diseases, especially atherosclerosis, 3 hypertension, 4 diabetes, 5 and some other conditions, including cigarette smoking, 6 alcohol, 7 high fat diet, 8 and aging, 9 which can accelerate endothelial dysfunction. Dysfunction of endothelium is characterized by not only alternation of morphology and motility but also changes in endothelial behaviors, including an imbalance in the relative contribution of endothelium-derived relaxing and contracting factors, 10 disrupted vascular tone, 11 increased vascular permeability-induced inflammatory reactions, 3 which contributes to regulate development of thrombus formation, 12 atherosclerosis, 3 vascular restenosis, 13 arterial aneurysm, 14 and arterial stiffness.…”