Francesco Paneni1, Sarah Costantino2, Francesco Cosentino3. 1. Cardiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden; Cardiology, Department of Clinical and Molecular Medicine, University of Rome "Sapienza", Italy. 2. Cardiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden. 3. Cardiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden. Electronic address: francesco.cosentino@ki.se.
Abstract
OBJECTIVE: Obesity-induced insulin resistance (IR) precipitates cardiovascular disease (CVD). Impairment of insulin signalling in the endothelium is emerging as a trigger of IR but the underlying mechanisms remain elusive. The mitochondrial adaptor p66(Shc) drives endothelial dysfunction via reactive oxygen species (ROS) generation. This study investigates p66(Shc) role in obesity-induced impairment of endothelial insulin signalling. METHODS: All experiments were performed in leptin-deficient (Lep(Ob/Ob)) and wild-type (WT) mice. RESULTS: Endothelium-dependent relaxations to insulin were blunted in Lep(Ob/Ob) as compared to WT. Interestingly, in vivo gene silencing of p66(Shc) restored insulin response via IRS-1/Akt/eNOS pathway. Furthermore, p66(Shc) knockdown in endothelial cells isolated from Lep(Ob/Ob) mice attenuated ROS production, free fatty acids (FFA) oxidation and prevented dysregulation of redox-sensitive pathways such as nuclear factor-kappa-B (NF-kB), AGE precursor methylglyoxal and PGI2 synthase. CONCLUSIONS: Targeting endothelial p66(Shc) may represent a promising strategy to prevent IR and CVD in obese individuals.
OBJECTIVE: Obesity-induced insulin resistance (IR) precipitates cardiovascular disease (CVD). Impairment of insulin signalling in the endothelium is emerging as a trigger of IR but the underlying mechanisms remain elusive. The mitochondrial adaptor p66(Shc) drives endothelial dysfunction via reactive oxygen species (ROS) generation. This study investigates p66(Shc) role in obesity-induced impairment of endothelial insulin signalling. METHODS: All experiments were performed in leptin-deficient (Lep(Ob/Ob)) and wild-type (WT) mice. RESULTS: Endothelium-dependent relaxations to insulin were blunted in Lep(Ob/Ob) as compared to WT. Interestingly, in vivo gene silencing of p66(Shc) restored insulin response via IRS-1/Akt/eNOS pathway. Furthermore, p66(Shc) knockdown in endothelial cells isolated from Lep(Ob/Ob) mice attenuated ROS production, free fatty acids (FFA) oxidation and prevented dysregulation of redox-sensitive pathways such as nuclear factor-kappa-B (NF-kB), AGE precursor methylglyoxal and PGI2 synthase. CONCLUSIONS: Targeting endothelial p66(Shc) may represent a promising strategy to prevent IR and CVD in obese individuals.
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