NADPH oxidase is related with lipid peroxidation and redox-sensitive kinase activation in human failing hearts

Increased superoxide generation by NADPH oxidase is implicated in the pathophysiology of human heart failure. The events downstream to NADPH oxidase activation remains undefined in human end-stage hearts and available information is restricted to the left ventricle (LV). We investigated NADPH oxidase activity, lipid peroxidation and activation of three mitogen-activated protein kinases (extracellular signal-regulated kinase, ERK1/2, c-jun N-terminal kinase, JNK and p-38) in the right (RV) and left ventricle of hearts explanted for terminal heart failure in order to establish a possible association among these factors. Diseased LV and RV showed a significant increase in NADPH-oxidase activity compared to control ventricles. This increase was not associated with an augmented expression of its catalytic subunit, gp91phox, but to membrane translocation of p47phox , its regulatory subunit which modulates the activity of this oxidase. In fact, increase in NADPH-oxidase activity positively correlated with p47phox membrane translocation in both ventricles (RV: r=0.76, p<0.001; LV: r=0.79, p<0.001). Interestingly, in diseased RV NADPH oxidase activity was positively related to the respective pulmonary arterial pressure (PAP; r= 0.86, P=0.0014), suggesting that mechanical overstretch of the RV could be a cause of the increased activity of this enzyme. Lipid peroxidation, assessed by MDA levels, was also enhanced and ERK and p-38, but not JNK, activated. Moreover, for all considered factors, 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). Notwithstanding a mechanistic interpretation of the events downstream to NADPH oxidase activation is prevented in human end-stage hearts our results suggests a close association among superoxide production, p47phox translocation, lipid peroxidation and phosphorylation of specific MAP kinases. Another important observation is the correlation between the left and right ventricle from the same patient, a report of scientific and prospectively clinical relevance. In conclusion our data strongly suggest that oxidative stress may contribute to harmful RV (besides LV) remodelling, therefore advancing knowledge about molecular and functional characteristics of the right ventricle might lead to progress in the treatment of cardiomyopathy.