Monoamine Oxidase Is Overactivated in Left and Right Ventricles from Ischemic Hearts: An Intriguing Therapeutic Target

Abstract

Growing evidence indicates that reactive oxygen species (ROS) may play a key role in human heart failure (HF). Monoamine oxidase (MAO) is emerging as a major ROS source in several cardiomyopathies. However, little is known about MAO activity in human failing heart and its relationship with redox imbalance. Therefore, we measured MAO activity in the left (LV) and in the right (RV) ventricle of human nonfailing (NF) and in end-stage ischemic (IHD) and nonischemic failing hearts. We found that both MAO isoforms (MAO-A/B) significantly increased in terms of activity and expression levels only in IHD ventricles. Catalase and aldehyde dehydrogenase-2 activities (ALDH-2), both implicated in MAO-catalyzed catecholamine catabolism, were significantly elevated in the failing LV, whereas, in the RV, statistical significance was observed only for ALDH-2. Oxidative stress markers levels were significantly increased only in the failing RV. Actin oxidation was significantly elevated in both failing ventricles and related to MAO-A activity and to functional parameters. These data suggest a close association between MAO-A-dependent ROS generation, actin oxidation, and ventricular dysfunction. This latter finding points to a possible pathogenic role of MAO-A in human myocardial failure supporting the idea that MAO-A could be a new therapeutic target in HF.

Figure 1

Total MAO activity in RV and LV of nonfailing (NF) and failing hearts secondary to ischemic (IHD) and nonischemic (non-IHD) diseases. Data are expressed as mean ± SEM. Comparison is performed using ANOVA followed by Dunnett's post hoc test. ^∗∗ p < 0.01 IHD RV versus NF RV; ^∗ p < 0.05 IHD LV versus NF LV. n = 7 NF; n = 13 IHD; n = 8 non-IHD.

Figure 2

MAO isoform (MAO-A and B) activity (a, b) and expression (c, d) in RV and LV of NF and failing IHD ventricles. Data are expressed as mean ± SEM. ^∗ p < 0.05 failing versus NF. n = 7 NF; n = 13 IHD. Representative immunoblots (c) and densitometric quantification (d) of ratio of MAO to β-actin protein expression expressed as fold increase of IHD with respect to NF = 1. ^∗ p < 0.05 failing versus NF; ^∗∗ p < 0.01 failing versus NF.

Figure 3

Catalase (a) and ALDH-2 activity (b) in RV and LV of NF and failing IHD ventricles. Data are expressed as mean ± SEM. ^∗ p < 0.05 failing versus NF LV; ^∗∗ p < 0.01 failing versus NF LV; ^∗∗∗ p < 0.001 failing versus NF RV. n = 7 NF; n = 13 IHD.

Figure 4

Oxidative stress markers. MDA (a) and protein carbonyls (b) content in RV and LV of NF and failing IHD ventricles. Data are expressed as mean ± SEM. ^∗ p < 0.05 failing versus NF LV; ^∗∗ p < 0.01 failing versus NF RV. Actin carbonylation was obtained subjecting derivatized cardiac proteins to SDS-PAGE and immunoblot with anti-DNP antibodies (Oxyblot) (c) followed by stripping and reprobing with anti-actin antibodies (d). Actin oxidation index (e) is given by the ratio between the densitometric values of the bands in the Oxyblot and those of the corresponding bands in the anti-actin immunoblot; ^∗ p < 0.05 failing versus NF. n = 7 NF; n = 13 IHD.

Figure 5

Actin oxidation index and MAO-A activity are correlated to functional parameters in RV and LV of failing IHD ventricles. LV actin oxidation index is significantly correlated with LV MAO-A activity and pulmonary capillary wedge pressure (PCWP) as well as RV actin oxidation index with RV MAO-A activity and pulmonary artery pressure (PAP). n = 13 IHD.