Damien Denimal1, Serge Monier2, Marie-Claude Brindisi2, Jean-Michel Petit2, Benjamin Bouillet2, Amandine Nguyen2, Laurent Demizieux2, Isabelle Simoneau2, Jean-Paul Pais de Barros2, Bruno Vergès2, Laurence Duvillard2. 1. From the University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., A.N., L.D., I.S., B.V., L.D.); INSERM, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., L.D., I.S., J.-P.P.d.B., B.V., L.D.); Department of Biochemistry, University Hospital Dijon-Burgundy, Dijon, France (D.D., L.D.); Department of Endocrinology and Metabolic Diseases, University Hospital Dijon-Burgundy, Dijon, France (M.-C.B., J.-M.P., B.B., A.N., I.S., B.V.); and Lipidomic Analytical Platform, Bâtiment B3, Dijon, France (J.-P.P.d.B.). damien.denimal@chu-dijon.fr. 2. From the University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., A.N., L.D., I.S., B.V., L.D.); INSERM, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., L.D., I.S., J.-P.P.d.B., B.V., L.D.); Department of Biochemistry, University Hospital Dijon-Burgundy, Dijon, France (D.D., L.D.); Department of Endocrinology and Metabolic Diseases, University Hospital Dijon-Burgundy, Dijon, France (M.-C.B., J.-M.P., B.B., A.N., I.S., B.V.); and Lipidomic Analytical Platform, Bâtiment B3, Dijon, France (J.-P.P.d.B.).
Abstract
OBJECTIVE: High-density lipoprotein (HDL) from nondiabetic patients with metabolic syndrome (MetS) displays abnormalities in their lipidome, such as triglyceride enrichment and sphingosine-1-phosphate depletion. We hypothesized that these abnormalities could impair the ability of HDL to stimulate endothelial nitric oxide synthase (eNOS). APPROACH AND RESULTS: Compared with HDL from control subjects, HDL from normoglycemic patients with MetS was 39% richer in triglycerides (P<0.01) and 15% poorer in sphingosine-1-phosphate (P<0.05; n=23 in each group). eNOS activity, assessed by the conversion of L-[3H]arginine to L-[3H]citrulline, was 69% lower in human umbilical vein endothelial cells incubated with HDL from MetS patients than in cells incubated with HDL from controls (P<0.0001). In addition, the activating phosphorylation of eNOS at serine (Ser) 1177 and of Akt (protein kinase B) at Ser473 was 37% (P<0.001) and 39% (P<0.05) lower, respectively, with HDL from MetS patients. Sphingosine-1-phosphate enrichment of HDL from MetS patients restored their ability to stimulate eNOS activity (P<0.05), in relation with a significant increase in eNOS phosphorylation at Ser1177 (P<0.05) and in Akt phosphorylation at Ser473 (P=0.05). By contrast, triglyceride enrichment of HDL from control subjects did not modify eNOS activity (P=0.90) and phosphorylation at Ser1177 (P=0.87). CONCLUSIONS: We provide evidence that the activation of eNOS by HDL is decreased in MetS patients before the appearance of diabetes mellitus and that sphingosine-1-phosphate depletion of HDL is the main factor responsible for this defect. This has important consequences on the impairment of HDL functionality and antiatherogenic properties in these patients.
OBJECTIVE: High-density lipoprotein (HDL) from nondiabeticpatients with metabolic syndrome (MetS) displays abnormalities in their lipidome, such as triglyceride enrichment and sphingosine-1-phosphate depletion. We hypothesized that these abnormalities could impair the ability of HDL to stimulate endothelial nitric oxide synthase (eNOS). APPROACH AND RESULTS: Compared with HDL from control subjects, HDL from normoglycemic patients with MetS was 39% richer in triglycerides (P<0.01) and 15% poorer in sphingosine-1-phosphate (P<0.05; n=23 in each group). eNOS activity, assessed by the conversion of L-[3H]arginine to L-[3H]citrulline, was 69% lower in human umbilical vein endothelial cells incubated with HDL from MetS patients than in cells incubated with HDL from controls (P<0.0001). In addition, the activating phosphorylation of eNOS at serine (Ser) 1177 and of Akt (protein kinase B) at Ser473 was 37% (P<0.001) and 39% (P<0.05) lower, respectively, with HDL from MetS patients. Sphingosine-1-phosphate enrichment of HDL from MetS patients restored their ability to stimulate eNOS activity (P<0.05), in relation with a significant increase in eNOS phosphorylation at Ser1177 (P<0.05) and in Akt phosphorylation at Ser473 (P=0.05). By contrast, triglyceride enrichment of HDL from control subjects did not modify eNOS activity (P=0.90) and phosphorylation at Ser1177 (P=0.87). CONCLUSIONS: We provide evidence that the activation of eNOS by HDL is decreased in MetS patients before the appearance of diabetes mellitus and that sphingosine-1-phosphate depletion of HDL is the main factor responsible for this defect. This has important consequences on the impairment of HDL functionality and antiatherogenic properties in these patients.
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311