title: Serelaxin Treatment Reduces Oxidative Stress and Increases Aldehyde Dehydrogenase-2 to Attenuate Nitrate Tolerance.
abstract: Background:Glyceryl trinitrate (GTN) is a commonly prescribed treatment for acute heart failure patients. However, prolonged GTN treatment induces tolerance, largely due to increased oxidative stress and reduced aldehyde dehydrogenase-2 (ALDH-2) expression. Serelaxin has several vasoprotective properties, which include reducing oxidative stress and augmenting endothelial function. We therefore tested the hypothesis in rodents that serelaxin treatment could attenuate low-dose GTN-induced tolerance.Methods and Results:Co-incubation of mouse aortic ringsex vivowith GTN (10 μM) and serelaxin (10 nM) for 1 h, restored GTN responses, suggesting that serelaxin prevented the development of GTN tolerance. Male Wistar rats were subcutaneously infused with ethanol (control), low-dose GTN+placebo or low-dose GTN+serelaxin via osmotic minipumps for 3 days. Aortic vascular function and superoxide levels were assessed using wire myography and lucigenin-enhanced chemiluminescence assay respectively. Changes in aortic ALDH-2 expression were measured by qPCR and Western blot respectively. GTN+placebo infusion significantly increased superoxide levels, decreased ALDH-2 and attenuated GTN-mediated vascular relaxation. Serelaxin co-treatment with GTN significantly enhanced GTN-mediated vascular relaxation, reduced superoxide levels and increased ALDH-2 expression compared to GTN+placebo-treated rats.Conclusion:Our data demonstrate that a combination of serelaxin treatment with low dose GTN attenuates the development of GTN-induced tolerance by reducing superoxide production and increasing ALDH-2 expression in the rat aorta. We suggest that serelaxin may improve nitrate efficacy in a clinical setting.
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville VIC, Australia.
authors.forename: Chen Huei
authors.initials: CH
authors.lastname: Leo
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville VIC, Australia.
authors.forename: Dhanushke T
authors.initials: DT
authors.lastname: Fernando
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville VIC, Australia.
authors.forename: Lillie
authors.initials: L
authors.lastname: Tran
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville VIC, Australia.
authors.forename: Hooi Hooi
authors.initials: HH
authors.lastname: Ng
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville VIC, Australia.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Marshall
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville VIC, Australia.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Parry
keywords: aldehyde dehydrogenase-2; aorta; nitrates; oxidative stress; serelaxin