Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury

Abstract

Recent evidence highlights monoamine oxidases (MAO) as another prominent source of oxidative stress. MAO are a class of enzymes located in the outer mitochondrial membrane, deputed to the oxidative breakdown of key neurotransmitters such as norepinephrine, epinephrine and dopamine, and in the process generate H(2)O(2). All these monoamines are endowed with potent modulatory effects on myocardial function. Thus, when the heart is subjected to chronic neuro-hormonal and/or peripheral hemodynamic stress, the abundance of circulating/tissue monoamines can make MAO-derived H(2)O(2) production particularly prominent. This is the case of acute cardiac damage due to ischemia/reperfusion injury or, on a more chronic stand, of the transition from compensated hypertrophy to overt ventricular dilation/pump failure. Here, we will first briefly discuss mitochondrial status and contribution to acute and chronic cardiac disorders. We will illustrate possible mechanisms by which MAO activity affects cardiac biology and function, along with a discussion as to their role as a prominent source of reactive oxygen species. Finally, we will speculate on why MAO inhibition might have a therapeutic value for treating cardiac affections of ischemic and non-ischemic origin. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.

Figure 1. Signaling pathways triggered by MAO-induced H₂O₂ formation

Increased H₂O₂ production by MAO can trigger different signaling pathways in different cell types. Lower levels of H₂O₂ activate ERK1/2, NFAT3/4 and MMPs in cardiac myocytes and vascular smooth muscle cells resulting in hypertrophy, cell proliferation and matrix remodeling. Instead, higher levels of MAO activity are associated with Bax upregulation, SphK inhibition, myofibrillar oxidation and mitochondrial dysfunction leading to cell death in heart failure or following ischemia/reperfusion. MAO: monoamine oxidase, ERK: extracellular signal regulated kinase, NFAT: nuclear factor of activated T cells, MMPs: metalloproteinases, SphK: sphingosine kinase.

Figure 2. Mechanism for MAO activation and consequent mitochondrial dysfunction in heart failure

Hyperadrenergic activation following a hypertrophic stimulus (such as pressure overload) results in increased availability of catecholamines for MAO-mediated degradation. This in turn leads to elevated H₂O₂ formation that can directly influence ventricular remodeling and myocardial function, but it may also target mitochondria resulting in permeability transition pore opening and ROS induced ROS release (RIRR), further amplifying the damage in the heart. It should not be excluded that other products of MAO activity, such as aldehydes and ammonia, may also participate to these processes.