title: NADPH oxidase-dependent redox signaling in human heart failure: relationship between the left and right ventricle.
abstract: Oxidative stress resulting from increased superoxide generation by NADPH oxidase is implicated in the pathophysiology of human heart failure. Downstream targets of NADPH oxidase remain undefined and available information is restricted to the left ventricle (LV). Thus, we aimed to assess the cascade of events triggered by increased NADPH oxidase activity (lipid peroxidation and activation of mitogen-activated protein kinases ERK1/2, JNK and p38) and their mutual relationship in right (RV) and (LV) of end-stage failing human hearts. When compared to control ventricles, diseased RV and LV showed a significant increase in NADPH oxidase superoxide production that positively correlated with p47(phox) membrane translocation (RV: r=0.76, P<0.001; LV: r=0.79, P<0.001). MDA content, a marker of lipid peroxidation, was also enhanced and ERK and p38, but not JNK, were activated. For all these relevant steps of the oxidative stress pathway, a significant correlation was observed between LV and RV from the same heart (NADPH-dependent superoxide production: r=0.678, P<0.0055; MDA: r=0.95, P<0.0001; p-p38/p38 ratio: r=0.926, P<0.0001; p-ERK/ERK ratio: r=0.913, P<0.0001). We concluded that in human heart failure, both ventricles are targets of NADPH oxidase superoxide generation which in turn may trigger the coordinated activation of downstream signaling components. This pathway may contribute to adverse remodeling of the LV and RV and subsequent progression toward end-stage heart failure, suggestive of new therapeutic targeting strategy.
authors.affiliation: Department of Biochemical Sciences, University of Florence, Viale Morgagni, 50, 50134 Florence, Italy. chiara.nediani@unifi.it
authors.forename: Chiara
authors.initials: C
authors.lastname: Nediani
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Borchi
authors.forename: Carla
authors.initials: C
authors.lastname: Giordano
authors.forename: Serena
authors.initials: S
authors.lastname: Baruzzo
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ponziani
authors.forename: Mariangela
authors.initials: M
authors.lastname: Sebastiani
authors.forename: Paolo
authors.initials: P
authors.lastname: Nassi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mugelli
authors.forename: Giulia
authors.initials: G
authors.lastname: d'Amati
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cerbai
mesh_terms: D000328:Adult; D000368:Aged; D018450:Disease Progression; D005260:Female; D006333:Heart Failure / Q000201:enzymology* / Q000209:etiology; D006352:Heart Ventricles / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology; D019255:NADPH Oxidases / Q000378:metabolism*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases