Recent advances on the role of monoamine oxidases in cardiac pathophysiology

Abstract

Numerous physiological and pathological roles have been attributed to the formation of mitochondrial reactive oxygen species (ROS). However, the individual contribution of different mitochondrial processes independently of bioenergetics remains elusive and clinical treatments unavailable. A notable exception to this complexity is found in the case of monoamine oxidases (MAOs). Unlike other ROS-producing enzymes, especially within mitochondria, MAOs possess a distinct combination of defined molecular structure, substrate specificity, and clinically accessible inhibitors. Another significant aspect of MAO activity is the simultaneous generation of hydrogen peroxide alongside highly reactive aldehydes and ammonia. These three products synergistically impair mitochondrial function at various levels, ultimately jeopardizing cellular metabolic integrity and viability. This pathological condition arises from exacerbated MAO activity, observed in many cardiovascular diseases, thus justifying the exploration of MAO inhibitors as effective cardioprotective strategy. In this context, we not only summarize the deleterious roles of MAOs in cardiac pathologies and the positive effects resulting from genetic or pharmacological MAO inhibition, but also discuss recent findings that expand our understanding on the role of MAO in gene expression and cardiac development.

Does Cell-Type-Specific Silencing of Monoamine Oxidase B Interfere with the Development of Right Ventricle (RV) Hypertrophy or Right Ventricle Failure in Pulmonary Hypertension?

“…MAO-B is known to produce ROS during oxidative deamination of neurotransmitters. In certain stress situations, like for left ventricular diseases, the importance of ROS generated by MAOs was already described [ 22 ]. To investigate the influence of MAO-B during RV pressure overload, intracellular ROS detection was performed for MAO-B fl/fl and cmMAO-B KO mice.…”

“…While the importance of MAOs in the pathophysiology of left ventricular diseases is well-established [ 19 , 20 , 21 , 22 ], data on their importance for RV diseases are rare, but involvement in PH has been proposed [ 23 ]. In rats, PH secondary to monocrotaline injection [ 24 ], sugen5416/hypoxia, or pulmonary artery banding [ 25 ] upregulates MAO-A expression in the pulmonary vasculature and the failing RV.…”

Mitochondrial calcium in cardiac ischemia/reperfusion injury and cardioprotection

“…In conclusion, although mitochondrial ROS production is increased also under hypoxic conditions, the largest quantity of ROS is produced during reperfusion, primarily via reverse electron transport at complex I. Besides the ETC, there are other important sources of ROS in mitochondria that have been implicated in I/R injury, such as monoamine oxidases (discussed in another review of this series [73]), NADPH oxidases [141], and p66 shc [119]. Oxidative stress, in concert with mitochondrial Ca 2+ overload, can trigger mitochondrial permeability transition and ROS-induced ROS release, exacerbating cellular damage and creating a substrate for ventricular arrhythmias during I/R injury.…”

Evidence that the monoamine oxidase B (MAO-B) plays a central role in the inotropic dysfunction induced by genetic deletion of the Mas-related-G protein-coupled receptor D (MrgD) in mice

“…The increased redox signaling potentially trigged by MAO-B observed in KO cardiac tissue (Figure 2) are commonly related to oxidizing myofilament proteins 49,50 , contributing to a higher degradation rate of myofilaments such as α-actin and myosin 51 .…”