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Molecular and functional effects of beta-adrenoceptors antagonism in the vascular dysfunction of obese mice

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Author(s):
Nathalia Santos da Silva
Total Authors: 1
Document type: Master's Dissertation
Defense date:
Abstract

In this study we hypothesized that blocking ß-adrenergic receptor (ß-AR) hyperactivation using the non-selective ß-AR antagonist propranolol would restore endothelial function in obesity by improving the nitric oxide (NO)-mediated endothelium-dependent vasodilation and by reducing expression of inflammatory markers. Male C57BL/6/JUnib mice (2 months old) fed a standard diet (C) or a high fat diet (HFD) for 8 weeks and were concomitantly treated with vehicle or propranolol (P) (10 mg/kg/day p.o.). The HFD increased body weight that was not modified by propranolol treatment. Heart rate was reduced in CP and HFP groups compared to groups C and HF. Systolic blood pressure increased in the last two weeks of the HFD feeding, but it was prevented in HFP group. There were no group differences in glycemia and in serum levels of total cholesterol, triglicerydes, adiponectin and glucagon. Leptinemia and insulinemia were increased in mice fed HFD compared to the C group. Propranolol treatment reduced insulinemia in HFP without affecting hiperleptinemia. Relaxation to acetylcholine (ACh) and insulin evaluated in aortic rings was impaired in mice fed HFD, whereas propranolol prevented these changes. Relaxation responses to sodium nitroprusside, isoproterenol and glucagon were not modified by either HFD or propranolol. The NO synthase (NOS) inhibitor L-NAME abolished the group differences in the vasodilatatory response to both ACh and insulin, suggesting a role for eNOS-derived NO in the vascular effects of propranolol in obese mice. In accordance NO production was reduced in the aorta of HF group, which was prevented in the HFP group. The Ser473Akt and Ser1177eNOS phosphorylation (p) was decreased in aorta of the HF group, while Ser307p-IRS-1 and Thr202/Tyr204p-ERK1/2's expression was increased; propranolol normalized these parameters in the HFP group. The phosphorylation of the nuclear factor-kB (NF-kB) inhibitory protein (Ser32p-IkB-'alpha') was increased in the HF group, while there was an increase in the total IkB-'alpha' and eNOS protein expression in aorta of the HFP group. The interleukin(IL)-6 expression was elevated in aorta of the HF group and propranolol prevented this increase. Therefore, the propranolol treatment 1) exhibited an anti-hypertensive effect, 2) increased NO bioavailability and the endothelium-dependent relaxation, 3) improved the vascular insulin relaxation and signaling and 4) attenuated the expression of inflammatory markers in the HFD-induced obese mice. These effects were independent of changes in body weight, suggesting a therapeutic potential for propranolol in the vascular complications associated with obesity (AU)

FAPESP's process: 15/00074-0 - Molecular and functional analysis of beta-adrenoceptors antagonism on the vascular alterations of obese mice
Grantee:Nathalia Santos da Silva
Support type: Scholarships in Brazil - Master