Endothelial Extracellular Signal‐Regulated Kinase/Thromboxane A2/Prostanoid Receptor Pathway Aggravates Endothelial Dysfunction and Insulin Resistance in a Mouse Model of Metabolic Syndrome

Abstract

Background Metabolic syndrome is characterized by insulin resistance, which impairs intracellular signaling pathways and endothelial NO bioactivity, leading to cardiovascular complications. Extracellular signal‐regulated kinase (ERK) is a major component of insulin signaling cascades that can be activated by many vasoactive peptides, hormones, and cytokines that are elevated in metabolic syndrome. The aim of this study was to clarify the role of endothelial ERK2 in vivo on NO bioactivity and insulin resistance in a mouse model of metabolic syndrome. Methods and Results Control and endothelial‐specific ERK2 knockout mice were fed a high‐fat/high‐sucrose diet (HFHSD) for 24 weeks. Systolic blood pressure, endothelial function, and glucose metabolism were investigated. Systolic blood pressure was lowered with increased NO products and decreased thromboxane A2/prostanoid (TP) products in HFHSD‐fed ERK2 knockout mice, and Nω‐nitro‐l‐arginine methyl ester (L‐NAME) increased it to the levels observed in HFHSD‐fed controls. Acetylcholine‐induced relaxation of aortic rings was increased, and aortic superoxide level was lowered in HFHSD‐fed ERK2 knockout mice. S18886, an antagonist of the TP receptor, improved endothelial function and decreased superoxide level only in the rings from HFHSD‐fed controls. Glucose intolerance and the impaired insulin sensitivity were blunted in HFHSD‐fed ERK2 knockout mice without changes in body weight. In vivo, S18886 improved endothelial dysfunction, systolic blood pressure, fasting serum glucose and insulin levels, and suppressed nonalcoholic fatty liver disease scores only in HFHSD‐fed controls. Conclusions Endothelial ERK2 increased superoxide level and decreased NO bioactivity, resulting in the deterioration of endothelial function, insulin resistance, and steatohepatitis, which were improved by a TP receptor antagonist, in a mouse model of metabolic syndrome.

Bioinformatics study of the potential therapeutic effects of ginsenoside Rh3 in reversing insulin resistance

“…MAPK1 assumes a crucial role in the regulation of diabetes and inflammation ( Ge et al, 2020 ). In mouse models of metabolic syndrome, ERK2 overexpression increased insulin resistance ( Sato et al, 2022 ), while endothelial ERK2 deletion improved insulin resistance ( Kujiraoka et al, 2022 ). Our results suggest that GRh3 may alleviate insulin resistance by downregulating MAPK1 expression.…”

Reactive Oxygen Species in the Aorta and Perivascular Adipose Tissue Precedes Endothelial Dysfunction in the Aorta of Mice with a High-Fat High-Sucrose Diet and Additional Factors

“…In order to understand the pathophysiology of Mets, a rodent model fed a high-fat and high-sucrose diet (HFHSD) has been used [ 2 , 3 , 4 , 5 ]. The contribution of HFHSD to insulin resistance depends on the strains of mice, and C57BL/6 mice were demonstrated to develop insulin resistance by HFHSD [ 6 ].…”

Thromboxane A2/thromboxane A2 receptor axis facilitates hepatic insulin resistance and steatosis through endoplasmic reticulum stress in non‐alcoholic fatty liver disease

“…The high‐affinity receptor activated by TXA 2 is called the TXA 2 receptor (TP receptor), a G‐protein coupled receptor located on the cell membrane, which is widely expressed in the thymus, spleen and liver (Nakahata, 2008). TP receptors have been reported to be activated in atherosclerosis and inflammation and play a critical role in endothelial dysfunction and insulin resistance (Eckenstaler et al, 2022; Sato et al, 2022). Our previous research has demonstrated that TXA 2 was elevated in obesity and that the TXA 2 –TP receptor axis promoted adipose tissue macrophage M1 polarization, leading to insulin resistance and facilitated excessive hepatic gluconeogenesis in the liver (Y. Dai et al, 2023; Xu et al, 2023).…”