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.

Extracts of Crataegus oxyacantha and Rosmarinus officinalis Attenuate Ischemic Myocardial Damage by Decreasing Oxidative Stress and Regulating the Production of Cardiac Vasoactive Agents

“…Moreover, Ang II an octapeptide considered a powerful vasoconstrictor is produced by the angiotensin-converting enzyme (ACE) and plays a very important role in the regulation of cardiac functions [ 35 , 36 ]. In fact, elevated concentrations of Ang II have been found in the infarcted area, which have correlated with decreased conductance among myocytes [ 9 ].…”

“…After 120 min of acute MI, the heart was cut out and the ischemic area separated to perform the analysis. A sham-operated group served as control [ 36 , 61 ].…”

“…Left ventricular functional examination was performed in the heart of rats specifically assigned to this experimental phase ( n = 6 per group) following a previously reported protocol [ 36 ]. The hearts were mounted into the Langendorff system and were perfused retrogradely via the aorta using a Grass stimulator (SIU5, Grass Instruments Co., Quincy, MA, USA).…”

“…For electron microscopy, ventricular tissue was fixed in 2.5% glutaraldehyde for 1 h, post-fixed in 1% osmium tetroxide, dehydrated with increasing concentrations of etanol and embeded in EPON 812 (Electron Microscopy Sciences, Hatfield, PA, USA). Ultrathin sections of 60 nm were cut using an Ultracut microtome (RMC pt XL, Boeckeler Instruments Inc., Tucson, AZ, USA); the sections were contrasted in uranyl acetate and lead citrate to be further examined with a JEM-1011 (JEOL Ltd., Tokyo, Japan) at 60 kV [ 36 ]. Random pictures of 2–3 myocardial ischemic areas were taken from three rats per group using 12,000× magnification for sarcomere and 20,000× magnification for mitochondria and nuclei.…”

“…Ang II, Ang-(1–7), and MDA production was evaluated in myocardial ischemic areas from different experimental groups by capillary zone electrophoresis (CZE, P/ACE MDQ Capillary Electrophoresis System, Beckman Coulter, Inc., Fullerton, CA, USA) according to the methods described previously [ 36 ]. The production of BH 4 and BH 2 was determined by CZE as previously reported by Oidor-Chan et al [ 44 ].…”