NADPH oxidase-dependent redox signaling in human heart failure: relationship between the left and right ventricle.
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.
Nediani
Chiara
C
Department of Biochemical Sciences, University of Florence, Viale Morgagni, 50, 50134 Florence, Italy. chiara.nediani@unifi.it
Borchi
Elisabetta
E
Giordano
Carla
C
Baruzzo
Serena
S
Ponziani
Vanessa
V
Sebastiani
Mariangela
M
Nassi
Paolo
P
Mugelli
Alessandro
A
d'Amati
Giulia
G
Cerbai
Elisabetta
E
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
D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases