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

Manni, Maria Elena; Rigacci, Stefania; Borchi, Elisabetta; Bargelli, Valentina; Miceli, Caterina; Giordano, Carla; Raimondi, Laura; Nediani, Chiara

doi:10.1155/2016/4375418

Cited by 42 publications

(40 citation statements)

References 57 publications

(71 reference statements)

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“…Here, we demonstrate that chronic sublethal doses of H 2 O 2 produced by MAO‐A in response to its endogenous (NE) or exogenous (Tyr) substrates can recapitulate all the features of senescence. This could have particular relevance in cardiac ageing, where MAO‐A is likely to be chronically activated due to: (a) sympathetic activation and enhanced release of norepinephrine from adrenergic nerves (Santulli & Iaccarino, 2016); and (b) overexpression of MAO‐A in the ageing heart (as shown in Figure 1a,b) or in age‐associated cardiac diseases (Manni et al, 2016; Villeneuve et al, 2013). In addition, the role of MAO‐A in senescence could be extended to different cell types, since MAO‐A has been characterized in many proliferative cells, such as fibroblasts and bone marrow mesenchymal stem cells, where its expression was significantly increased during ageing (Edelstein & Breakefield, 1986; Trouche et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

et al. 2018

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Cellular senescence, the irreversible cell cycle arrest observed in somatic cells, is an important driver of age‐associated diseases. Mitochondria have been implicated in the process of senescence, primarily because they are both sources and targets of reactive oxygen species (ROS). In the heart, oxidative stress contributes to pathological cardiac ageing, but the mechanisms underlying ROS production are still not completely understood. The mitochondrial enzyme monoamine oxidase‐A (MAO‐A) is a relevant source of ROS in the heart through the formation of H2O2 derived from the degradation of its main substrates, norepinephrine (NE) and serotonin. However, the potential link between MAO‐A and senescence has not been previously investigated. Using cardiomyoblasts and primary cardiomyocytes, we demonstrate that chronic MAO‐A activation mediated by synthetic (tyramine) and physiological (NE) substrates induces ROS‐dependent DNA damage response, activation of cyclin‐dependent kinase inhibitors p21cip, p16ink4a, and p15ink4b and typical features of senescence such as cell flattening and SA‐β‐gal activity. Moreover, we observe that ROS produced by MAO‐A lead to the accumulation of p53 in the cytosol where it inhibits parkin, an important regulator of mitophagy, resulting in mitochondrial dysfunction. Additionally, we show that the mTOR kinase contributes to mitophagy dysfunction by enhancing p53 cytoplasmic accumulation. Importantly, restoration of mitophagy, either by overexpression of parkin or inhibition of mTOR, prevents mitochondrial dysfunction and induction of senescence. Altogether, our data demonstrate a novel link between MAO‐A and senescence in cardiomyocytes and provides mechanistic insights into the potential role of MAO‐dependent oxidative stress in age‐related pathologies.

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Section: Discussionmentioning

confidence: 99%

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

et al. 2018

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“…MAO-A is an isoform of FAD-dependent enzymes, that catalyzes oxidative deamination of catecholamines and serotonin in the heart, producing the corresponding aldehyde, H 2 O 2 , and ammonia. Previous studies have reported that MAO-A expression and activity increased in chronic cardiac diseases [108][109][110][111]. They found that OleA conferred cardioprotection, not simply by its antioxidant action, but through restoration of defective autophagic flux autophagy, reflected by auto-phagolysosome formation, measured by p62 and cathepsin-B levels increase, and the transcriptional factor EB (TFEB) activation and translocation to the nucleus.…”

Section: Oleuropein and Cardioprotectionmentioning

confidence: 99%

Oleuropein, a Bioactive Compound from Olea europaea L., as a Potential Preventive and Therapeutic Agent in Non-Communicable Diseases

et al. 2019

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Growing scientific literature data suggest that the intake of natural bioactive compounds plays a critical role in preventing or reducing the occurrence of human chronic non-communicable diseases (NCDs). Oleuropein, the main phenolic component of Olea europaea L., has attracted scientific attention for its several health beneficial properties such as antioxidant, anti-inflammatory, cardio- and neuro-protective, and anti-cancer. This article is a narrative review focused on the current literature concerning the effect of oleuropein in NCDs, such as neuro- and cardiovascular diseases, diabetes mellitus, chronic kidney diseases, and cancer, by its putative antioxidant and anti-inflammatory activity, but also for its other peculiar actions such as an autophagy inducer and amyloid fibril growth inhibitor and, finally, for its anti-cancer effect. Despite the increasing number of published studies, looking at the beneficial effects of oleuropein, there is limited clinical evidence focused on the benefits of this polyphenol as a nutraceutical product in humans, and many problems are still to be resolved about its bioavailability, bioaccessibility, and dosage. Thus, future clinical randomized trials are needed to establish the relation between the beneficial effects and the mechanisms of action occurring in the human body in response to the intake of oleuropein.

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“…diovascular disease and Parkinsonʼs disease. MAO-A inhibitors have thus been advocated as potential treatment of congestive heart failure while MAO-B inhibitors may act as potential neuroprotective agents in neurodegenerative disorders [2,[11][12][13]. Interestingly, MAO-A activity has been found to be increased in certain types of cancer, and MAO-A inhibitors have thus been investigated as potential treatment of prostate cancer [14].…”

Section: Monoamine Oxidase Inhibition By Kavalactones From Kava (Pipementioning

confidence: 99%

Monoamine Oxidase Inhibition by Kavalactones from Kava (Piper Methysticum)

et al. 2019

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Monoamine oxidases (MAOs) are key metabolic enzymes for neurotransmitter and dietary amines and are targets for the treatment of neuropsychiatric and neurodegenerative disorders. This study examined the MAO inhibition potential of kavain and other kavalactones from the roots of kava (Piper methysticum), a plant that has been used for its anxiolytic properties. (±)-Kavain was found to be a good potency in vitro inhibitor of human MAO-B with an IC50 of 5.34 µM. (±)-Kavain is a weaker MAO-A inhibitor with an IC50 of 19.0 µM. Under the same experimental conditions, the reference MAO inhibitor, curcumin, displays IC50 values of 5.01 µM and 2.55 µM for the inhibition of MAO-A and MAO-B, respectively. It was further established that (±)-kavain interacts reversibly and competitively with MAO-A and MAO-B with enzyme-inhibitor dissociation constants (Ki) of 7.72 and 5.10 µM, respectively. Curcumin in turn, displays a Ki value of 3.08 µM for the inhibition of MAO-A. Based on these findings, other kavalactones (dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin) were also evaluated as MAO inhibitors in this study. Yangonin proved to be the most potent MAO inhibitor with IC50 values of 1.29 and 0.085 µM for MAO-A and MAO-B, respectively. It may be concluded that some of the central effects (e.g., anxiolytic) of kava may be mediated by MAO inhibition.

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

Cited by 42 publications

References 57 publications

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

Oleuropein, a Bioactive Compound from Olea europaea L., as a Potential Preventive and Therapeutic Agent in Non-Communicable Diseases

Monoamine Oxidase Inhibition by Kavalactones from Kava (Piper Methysticum)

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