Monoamine Oxidase B Prompts Mitochondrial and Cardiac Dysfunction in Pressure Overloaded Hearts

Abstract

Aims: Monoamine oxidases (MAOs) are mitochondrial flavoenzymes responsible for neurotransmitter and biogenic amines catabolism. MAO-A contributes to heart failure progression via enhanced norepinephrine catabolism and oxidative stress. The potential pathogenetic role of the isoenzyme MAO-B in cardiac diseases is currently unknown. Moreover, it is has not been determined yet whether MAO activation can directly affect mitochondrial function. Results: In wild type mice, pressure overload induced by transverse aortic constriction (TAC) resulted in enhanced dopamine catabolism, left ventricular (LV) remodeling, and dysfunction. Conversely, mice lacking MAO-B (MAO-B -/ -) subjected to TAC maintained concentric hypertrophy accompanied by extracellular signal regulated kinase (ERK)1/2 activation, and preserved LV function, both at early (3 weeks) and late stages (9 weeks). Enhanced MAO activation triggered oxidative stress, and dropped mitochondrial membrane potential in the presence of ATP synthase inhibitor oligomycin both in neonatal and adult cardiomyocytes. The MAO-B inhibitor pargyline completely offset this change, suggesting that MAO activation induces a latent mitochondrial dysfunction, causing these organelles to hydrolyze ATP. Moreover, MAO-dependent aldehyde formation due to inhibition of aldehyde dehydrogenase 2 activity also contributed to alter mitochondrial bioenergetics. Innovation: Our study unravels a novel role for MAO-B in the pathogenesis of heart failure, showing that both MAO-driven reactive oxygen species production and impaired aldehyde metabolism affect mitochondrial function. Conclusion: Under conditions of chronic hemodynamic stress, enhanced MAO-B activity is a major determinant of cardiac structural and functional disarrangement. Both increased oxidative stress and the accumulation of aldehyde intermediates are likely liable for these adverse morphological and mechanical changes by directly targeting mitochondria. Antioxid. Redox Signal. 20, 267-280.

Histamine H4-Receptors Inhibit Mast Cell Renin Release in Ischemia/Reperfusion via Protein Kinase Cε-Dependent Aldehyde Dehydrogenase Type-2 Activation

“…Resident cardiac mast cells could take up serotonin released from platelets in I/R, leading to MAO activation (Shimizu et al, 2002). Furthermore, it was recently reported that a combination of MAO activation and ALDH2 inhibition by small interfering RNA generates H 2 O 2 and toxic aldehydes, leading to mitochondrial dysfunction and cell death in heart failure (Kaludercic et al, 2010(Kaludercic et al, , 2014. Accordingly, H 4 Rinduced ALDH2 activation could play an important cardioprotective mechanism by decreasing MAO-produced toxic aldehydes and preventing myocardial damage.…”

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

“…In cardiac myocytes, ROS are a byproduct of mitochondrial electron transport (5) and are also produced by extramitochondrial sources, including NADPH oxidase (1), uncoupled nitric oxide synthase (6), xanthine oxidase (7), and monoamine oxidase (8,9). Both mitochondrial and extramitochondrial sources have been implicated in cardiac disorders including heart failure, myocardial ischemia, and arrhythmias.…”

The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction

“…It has also been shown that MAO regulates the lipid peroxidation and other changes leading to cell death through reactive oxygen species 40. Inhibition of MAO‐B results in reduced formation of H 2 O 2 and aldehydes, two molecules that are known to stimulate mitochondrial and myocardial damage 41. Furthermore, in context with oxidative stress, we also explored SUMO‐1 which has been found to be highly relevant in the response to cellular stress and rescues SERCA2a ATPase (cardiac isoform of sarcoplasmic reticulum calcium ATPase) activity in heart failure 42, 43.…”

“…MAOs are able to trigger different signaling pathways leading to proliferation, apoptosis, or cell death, respectively 4. The potential of their inhibition in the heart during chronic neuro‐hormonal or hemodynamic stress can be directly associated with MAO‐derived H 2 O 2 and oxidative stress40, 41 or apoptosis reduction as well as mitochondrial viability either through Bcl2 and protein kinase C activation or Bax and caspase‐3 down‐regulation 8, 10, 12, 16. According to our findings we believe that RG preserved myocardial performance through several signaling pathways targeting oxidative stress, cardiomyocyte apoptosis, and favourable matrix remodeling.…”