Introduction: Leptin deficiency in mice (LepOb/Ob) triggers high caloric intake leading to obesity and insulin resistance. This condition activates several pathways generating reactive oxygen species (ROS). In this regard, recent evidence suggests that mitochondrial adaptor protein p66Shc is a crucial player in ROS-mediated cardiac and vascular damage. Hypothesis: We assessed whether p66Shc deletion (p66Shc-/-) protects against ROS-dependent endothelial dysfunction in a well-established model of obesity and insulin resistance. Methods: We studied three groups of male mice (C57/B6, 4-6 months old): 1) wild-type (WT), 2) leptin-deficient (p66Shc-LepOb/Ob), 3) double-mutant (p66Shc-/-/LepOb/Ob; n=10 per group). Animals were euthanized and plasma was collected for glucose, insulin, lipid and 8-iso-prostaglandin-F2α (8-iso-PGF2α) measurements. Endothelium-dependent relaxations to acetylcholine (Ach, 10-9-10-6 mol/L) were assessed in isolated aortic rings by organ chamber experiments. The nitric oxide donor sodium nitroprusside (SNP, 10-10-10-5 mol/L,) was used to test endothelium-independent responses. Results: Both p66Shc-LepOb/Ob and p66Shc-/-/LepOb/Ob showed similar increase in body weight, glycemia, total cholesterol, triglycerides and insulin compared with WT mice. Levels of 8-iso-PGF2α, a marker of oxidative stress, were higher in LepOb/Ob than WT (338±115 vs 210±48 pg/ml, p<0.05), whereas a significant reduction was found in p66Shc-/-/LepOb/Ob mice (204±124 pg/mL vs LepOb/Ob, p<0.05). Endothelium-dependent relaxations to Ach were impaired in p66Shc-LepOb/Ob mice (max relaxations: 67±1% vs 87±8% in WT, p<0.05). However, in leptin deficient mice with p66Shc genetic deletion endothelial function was preserved (max relaxations: 90±6% vs 67±1% in p66Shc-LepOb/Ob, p<0.01). Responses to SNP did not differ among the experimental groups. Conclusions: In the present study we demonstrate that obese mice lacking p66Shc are protected from ROS-driven endothelial dysfunction. Our findings suggest that p66Shc is a promising target to improve vascular dysfunction in the setting of obesity and insulin resistance.
Insulin resistant mice lacking p66Shc Gene are protected against endothelial dysfunction / Francesco, Paneni; Capretti, Giuliana; Enrico Di, Stasio; Alexander, Akhmedov; Giovanna, Petrucci; Enrico, Perna; Elena, Osto; Thomas Felix, Luscher; Volpe, Massimo; Cosentino, Francesco. - In: CIRCULATION. - ISSN 0009-7322. - 124:(2011). (Intervento presentato al convegno American Heart Association (AHA) 2011 Scientific Sessions tenutosi a Orlando, Florida nel 12-16 novembre 2011).
Insulin resistant mice lacking p66Shc Gene are protected against endothelial dysfunction
CAPRETTI, GIULIANA;VOLPE, Massimo;COSENTINO, Francesco
2011
Abstract
Introduction: Leptin deficiency in mice (LepOb/Ob) triggers high caloric intake leading to obesity and insulin resistance. This condition activates several pathways generating reactive oxygen species (ROS). In this regard, recent evidence suggests that mitochondrial adaptor protein p66Shc is a crucial player in ROS-mediated cardiac and vascular damage. Hypothesis: We assessed whether p66Shc deletion (p66Shc-/-) protects against ROS-dependent endothelial dysfunction in a well-established model of obesity and insulin resistance. Methods: We studied three groups of male mice (C57/B6, 4-6 months old): 1) wild-type (WT), 2) leptin-deficient (p66Shc-LepOb/Ob), 3) double-mutant (p66Shc-/-/LepOb/Ob; n=10 per group). Animals were euthanized and plasma was collected for glucose, insulin, lipid and 8-iso-prostaglandin-F2α (8-iso-PGF2α) measurements. Endothelium-dependent relaxations to acetylcholine (Ach, 10-9-10-6 mol/L) were assessed in isolated aortic rings by organ chamber experiments. The nitric oxide donor sodium nitroprusside (SNP, 10-10-10-5 mol/L,) was used to test endothelium-independent responses. Results: Both p66Shc-LepOb/Ob and p66Shc-/-/LepOb/Ob showed similar increase in body weight, glycemia, total cholesterol, triglycerides and insulin compared with WT mice. Levels of 8-iso-PGF2α, a marker of oxidative stress, were higher in LepOb/Ob than WT (338±115 vs 210±48 pg/ml, p<0.05), whereas a significant reduction was found in p66Shc-/-/LepOb/Ob mice (204±124 pg/mL vs LepOb/Ob, p<0.05). Endothelium-dependent relaxations to Ach were impaired in p66Shc-LepOb/Ob mice (max relaxations: 67±1% vs 87±8% in WT, p<0.05). However, in leptin deficient mice with p66Shc genetic deletion endothelial function was preserved (max relaxations: 90±6% vs 67±1% in p66Shc-LepOb/Ob, p<0.01). Responses to SNP did not differ among the experimental groups. Conclusions: In the present study we demonstrate that obese mice lacking p66Shc are protected from ROS-driven endothelial dysfunction. Our findings suggest that p66Shc is a promising target to improve vascular dysfunction in the setting of obesity and insulin resistance.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
