title: Fenofibrate Therapy Restores Antioxidant Protection and Improves Myocardial Insulin Resistance in a Rat Model of Metabolic Syndrome and Myocardial Ischemia: The Role of Angiotensin II.
abstract: Renin-angiotensin system (RAS) activation promotes oxidative stress which increases the risk of cardiac dysfunction in metabolic syndrome (MetS) and favors local insulin resistance. Fibrates regulate RAS improving MetS, type-2 diabetes and cardiovascular diseases. We studied the effect of fenofibrate treatment on the myocardic signaling pathway of Angiotensin II (Ang II)/Angiotensin II type 1 receptor (AT1) and its relationship with oxidative stress and myocardial insulin resistance in MetS rats under heart ischemia. Control and MetS rats were assigned to the following groups: (a) sham; (b) vehicle-treated myocardial infarction (MI) (MI-V); and (c) fenofibrate-treated myocardial infarction (MI-F). Treatment with fenofibrate significantly reduced triglycerides, non-high density lipoprotein cholesterol (non-HDL-C), insulin levels and insulin resistance index (HOMA-IR) in MetS animals. MetS and MI increased Ang II concentration and AT1 expression, favored myocardial oxidative stress (high levels of malondialdehyde, overexpression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), decreased total antioxidant capacity and diminished expression of superoxide dismutase (SOD)1, SOD2 and catalase) and inhibited expression of the insulin signaling cascade: phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PkB, also known as Akt)/Glut-4/endothelial nitric oxide synthase (eNOS). In conclusion, fenofibrate treatment favors an antioxidant environment as a consequence of a reduction of the Ang II/AT1/NOX4 signaling pathway, reestablishing the cardiac insulin signaling pathway. This might optimize cardiac metabolism and improve the vasodilator function during myocardial ischemia.
authors.affiliation: Department of Pharmacology, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico. luzibarralara@gmail.com.
authors.forename: Luz
authors.initials: L
authors.lastname: Ibarra-Lara
authors.affiliation: Department of Pharmacology, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico. msanchezaguilar@gmail.com.
authors.forename: María
authors.initials: M
authors.lastname: Sánchez-Aguilar
authors.affiliation: Department of Pharmacology, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico. masanchez@gmail.com.
authors.forename: Alicia
authors.initials: A
authors.lastname: Sánchez-Mendoza
authors.affiliation: Department of Pharmacology, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico. leonardodvm65@hotmail.com.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Del Valle-Mondragón
authors.affiliation: Department of Pathology, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico. sorieli@hotmail.com.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Soria-Castro
authors.affiliation: Department of Molecular Biology, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico. qfbelizabethcm@yahoo.es.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Carreón-Torres
authors.affiliation: Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y de la Nutrición "Salvador Zubirán", Vasco de Quiroga 15, Sección XVI, Tlalpan, México City 14000, Mexico. eulisesd@yahoo.com.
authors.forename: Eulises
authors.initials: E
authors.lastname: Díaz-Díaz
authors.affiliation: Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, México City 04510, Mexico. hvazquez@bq.unam.mx.
authors.forename: Héctor
authors.initials: H
authors.lastname: Vázquez-Meza
authors.affiliation: Department of Physiology, Instituto Nacional de Cardiología "Ignacio Chávez", Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico. gualanv@yahoo.com.
authors.forename: Verónica
authors.initials: V
authors.lastname: Guarner-Lans
authors.affiliation: Department of Physiology, Instituto Nacional de Cardiología "Ignacio Chávez", Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico. esther_rubio_ruiz@yahoo.com.
authors.forename: María Esther
authors.initials: ME
authors.lastname: Rubio-Ruiz
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D002374:Catalase / Q000097:blood; D004195:Disease Models, Animal; D011345:Fenofibrate / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy*; D009203:Myocardial Infarction / Q000188:drug therapy*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000097:blood; D000072105:Superoxide Dismutase-1 / Q000097:blood; D014280:Triglycerides / Q000097:blood; D000099156:Superoxide Dismutase 2
chemical_list: D000804:Angiotensin II; D000975:Antioxidants; D002374:Catalase; D011345:Fenofibrate; D007328:Insulin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D052250:Nitric Oxide Synthase Type III; D000081082:Phosphoinositide-3 Kinase Inhibitors; D044140:Receptor, Angiotensin, Type 1; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D014280:Triglycerides; D000099156:Superoxide Dismutase 2; C000606292:Sod1 protein, rat; C498911:Nox4 protein, rat
keywords: angiotensin II; fenofibrate; insulin resistance; metabolic syndrome; myocardial ischemia; oxidative stress