Abstract 19089: Endothelial Extracellular Signal-Regulated Kinase 2 Increases Blood Pressure and Induced Endothelial Dysfunction and Insulin Resistance in Mice With High Fat High Sucrose Diet

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Introduction: Metabolic syndrome (MetS) is well known as the risk of cardiovascular diseases associated with endothelial dysfunction, however, the mechanism is not fully clarified. Insulin resistance, and changes in various (adipo)cytokines are major characters of MetS, which affect intracellular signaling pathways and endothelial function. Extracellular signal-regulated kinase (ERK) is a major component of insulin signal and many of vasoactive peptides, which were released in MetS, can activate it in endothelium. However, the role of ERK in nitric oxide (NO) bioactivity in MetS in vivo has been unknown. The aim of this study is to clarify the role of endothelial ERK2 on NO bioactivity in MetS.

Methods and Results: We created endothelial specific ERK2 knock out mice (EE2KO) crossing Tie2-Cre mice and ERK2 flox mice and fed them with normal or high-fat/high-sucrose diet (HFHSD) for 24 weeks. Body weight and plasma glucose and lipids levels were not different between wild type (WT) and EE2KO with HFHSD. EE2KO with HFHSD lowered systolic blood pressure (WT: 123.7±5.83mmHg, EE2KO: 101.4±3.66mmHg, P<0.01, N=8) without changing heart rate. Endothelial function was assessed with the isometric tension measurement of aortic rings with acetylcholine (ACh). ACh-induced relaxation was improved in EE2KO with HFHSD and HOMA-IR was tended to increase in EE2KO with HFHSD. NO production assessed with plasma nitrite/nitrate concentrations were increased in EE2KO with HFHSD (WT: 23.10±3.74μmol/l, EE2KO: 41.71±6.73μmol/l, P<0.05, N=12).

Conclusions: Endothelial ERK2 increases systolic blood pressure and decreases NO bioactivity, resulted in deteriorating endothelial function and insulin resistance in mice model of MetS.

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