title: Mild caloric restriction reduces blood pressure and activates endothelial AMPK-PI3K-Akt-eNOS pathway in obese Zucker rats.
abstract: Genetic obesity models exhibit endothelial dysfunction associated to adenosine monophosphate-activated protein kinase (AMPK) dysregulation. This study aims to assess if mild short-term caloric restriction (CR) restores endothelial AMPK activity leading to an improvement in endothelial function. Twelve-week old Zucker lean and obese (fa/fa) male rats had access to standard chow either ad libitum (AL, n=8) or 80% of AL (CR, n=8) for two weeks. Systolic blood pressure was significantly higher in fa/fa AL rats versus lean AL animals, but was normalized by CR. Endothelium-dependent relaxation to acetylcholine (ACh, 10(-9) to 10(-4) M) was reduced in fa/fa AL compared to control lean AL rats (p<0.001), and restored by CR. The AMPK activator AICAR (10(-5) to 8·10(-3) M) elicited a lower relaxation in fa/fa AL rings that was normalized by CR (p<0.001). Inhibition of PI3K (wortmannin, 10(-7) M), Akt (triciribine, 10(-5) M), or eNOS (L-NAME, 10(-4) M) markedly reduced AICAR-induced relaxation in lean AL, but not in fa/fa AL rats. These inhibitions were restored by CR in Zucker fa/fa rings. These data show that mild short-term CR improves endothelial function and lowers blood pressure in obesity due to the activation of the AMPK-PI3K-Akt-eNOS pathway.
authors.affiliation: Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU-San Pablo, 28668 Madrid, Spain.
authors.forename: C F
authors.initials: CF
authors.lastname: García-Prieto
authors.affiliation: Instituto Pluridisciplinar and Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain; Unidad de Hipertensión, imas12, Hospital 12 de Octubre, 28041 Madrid, Spain.
authors.forename: H
authors.initials: H
authors.lastname: Pulido-Olmo
authors.affiliation: Instituto Pluridisciplinar and Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain; Unidad de Hipertensión, imas12, Hospital 12 de Octubre, 28041 Madrid, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Ruiz-Hurtado
authors.affiliation: Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU-San Pablo, 28668 Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Gil-Ortega
authors.affiliation: Instituto Pluridisciplinar and Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain; Departamento de Bioquímica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Aranguez
authors.affiliation: Servicio de Endocrinología y Nutrición, Hospital Clínico San Carlos, IdISSC, 28040 Madrid, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Rubio
authors.affiliation: Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU-San Pablo, 28668 Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Ruiz-Gayo
authors.affiliation: Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU-San Pablo, 28668 Madrid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Somoza
authors.affiliation: Instituto Pluridisciplinar and Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain. Electronic address: marisolf@farm.ucm.es.
authors.forename: M S
authors.initials: MS
authors.lastname: Fernández-Alfonso
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D031204:Caloric Restriction; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000178:diet therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011924:Rats, Zucker
chemical_list: D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases
keywords: Endothelial AMPK; Endothelial dysfunction; Mild short-term caloric restriction; Obesity