Role of Monoamine Oxidase A (MAO-A) in Cardiac Aging

Chandreyee Datta, Ashish Bhattacharjee*

Department of Biotechnology, National Institute of Technology, Durgapur, India

Among different sources that contribute in the global oxidative stress, the vast majority of cellular reactive oxygen species (ROS) originate from mitochondrial compartments. Recently, monoamine oxidases (MAOs) are identified as a prominent source of ROS. Monoamine oxidases are localized in the outer membrane of mitochondria and exist as two different isoforms, MAO-A and MAO-B. MAOs are mitochondrial flavoenzymes responsible for oxidative deamination of biogenic amines and during this process, H2O2 and aldehydes are generated as intermediate products. The role of monoamine oxidase in cardiovascular pathophysiology has only recently gained some attention as it is demonstrated that H2O2 and aldehydes may target myocardial function and consequently cardiac function. Results obtained by different research groups showed that MAO-A plays a key role in the regulation of physiological cardiac function and in the development of acute and chronic heart diseases through two mechanisms: regulation of substrate concentration and intracellular production of ROS. In this review, we will focus on the role of MAO-A in the field of cardiac aging and related diseases.

ROS: Reactive oxygen species; MAO: Monoamine oxidase; H2O2: Hydrogen peroxide; WHO: World Health Organization; TAC: Transverse aortic constriction; CLG: Clorgyline; Tyr: Tyramine; HF: Heart failure.

MAO-A is known as a pro-oxidative, mitochondrial membrane-bound enzyme which is widely distributed in all mammalian cell types except erythrocytes and encoded by X chromosome (Xp 11.23-11.4)1,2. This is a catalytically active flavoprotein which in the presence of molecular oxygen catalyzes oxidative deamination of biogenic and dietary amines like dopamine, nor-epinephrine, serotonin, tyramine, etc. and converts them into their corresponding aldehydes and ROS3-6. MAO-A has already been reported as a major contributor in the resolution of inflammation, cancer cell progression and metastasis7-10. It has also been reported as a signature marker of alternatively activated monocytes and macrophages8,11. Growing evidences have established the role of MAO-A in the pathogenesis of many cardiovascular disorders like myocardial injury12, heart failure13, vascular wall remodelling14 and cardiac cell apoptosis. Considering the role of MAOs in the cardiac pathology we will focus on the role of MAO-A in cardiac diseases. Aging is the progressive loss of tissue and organ function with respect to time13. Growing evidences from different experiments suggest that aging process to a larger extent is related to macromolecular damage (i.e. lipids, DNA and proteins) by reactive oxygen species (ROS) mostly affecting long lived post mitotic cells such as neurons and cardiac myocytes15. The exact mechanism of oxidative stress induced aging is still not clear but probably increased ROS levels lead to cellular senescence, a physiological mechanism, that stops cellular proliferation in response to damages that occur during replication.

Among different sources that contribute to global oxidative stress, vast majority of cellular ROS originate from (>90%) mitochondrial compartment. Recently, researchers have identified MAOs as a prominent source of ROS. Monoamine oxidase resides in the outer membrane of mitochondria. MAO-A and MAO-B these two isoforms are of great importance in the regulation of catecholamine and other biogenic amines in mammals. MAO-A appoint a FAD cofactor to catalyze oxidative deamination of various monoamines including different neurotransmitters (i.e serotonin, norepinephrine, dopamine) and some exogenous amines which are generally ingested by normal diets (tyramine) producing H2O2 and relative aldehydes as by-products.

In the aging process, reactive oxygen species occupy a very important position16,17. Multiple sources such as xanthine oxidase18, NADPH oxidase19 and mitochondrial respiratory chain20,21 can be involved in ROS generation. In case of aging process, the increase in the intracellular ROS and the oxidative stress dependent decline of cell functions are partially related to impairment of mitochondrial respiratory chain20-22. The mitochondrial flavoenzymes monoamine oxidase A and B (MAO-A & MAO-B) play a major role in oxidative de-amination of biogenic amines23. MAOs are also a major source of H2O2. Recent research has demonstrated that H2O2 generated by MAOs during substrate degradation is involved in cell proliferation24,25 and apoptosis26-28 -both are important events associated with aging process. The increase in the MAO activity has been associated with a detrimental structural and functional process of aging in some brain region29-31. So, an imbalance in MAO levels and activity may lead to neuropsychiatric disorders and also plays a pivotal role in the regulation of neurotransmitter. As MAOs have established themselves as a prominent source of ROS, it is believed that they may contribute to 63 various cardiovascular disorders, and also they can manipulate the aging process. According to the WHO report in 2013, a wide prevalence of cardiovascular disease is more common among persons aged > 65 years.

So, in this review, we will discuss :

1. Recently discovered roles of MAO-A in cardiac aging.

2. Role of mitochondrial ROS in cardiac aging.

3. Role of MAO-A as potential driver in cardiac aging.

In aging process, ROS play an important role16,17. Myocyte apoptosis and reactive hypertrophy contribute to the development of cardiac failure and heart aging, and increase in ROS production has been considered as one of the most important factors involved in these processes32-37. Furthermore, in the process of cardiac aging, impairment of cardiac metabolic and functional tolerance towards oxidative stress and decrease in some cardiac scavenger enzymes have been implicated38. Monoamine oxidase A and B are enzymes of great importance in the regulation of catecholamine and other biogenic amines in mammals. They are expressed in equivalent levels in human heart but differ significantly in rodents. MAO-A is the major isoform in rat heart and MAO-B is expressed in mouse heart39,40. MAOs appoint a FAD cofactor to catalyze oxidative deamination of several monoamines like various neurotransmitters serotonin, norepinephrine, and dopamine generating H2O2 and corresponding by products. Categorically, serotonin is a substrate of MAO-A but catecholamine can be oxidised by both isoforms41.

Recent researches have demonstrated that MAO-A and MAO-B are both identified as a major source of H2O2 and participate in progression of cardiac injury39. It has also been demonstrated that MAO-A expression and their ability to produce ROS increases with age42. This concept has become more evident with respect to the well documented tissue specific increase in MAO-A and MAO-B with respect to age. In aging heart, MAO-A level has been shown to increase around six fold and trigger cardiac damage42. Here, Maurel et al42 and his co-workers have studied H2O2 production in heart of young (1month), adult (3 and 6 months), and old (24 months) rats. Combined results from western blotting, semiquantitative real time PCR, Chemiluminescence assay (CL) and enzyme activity demonstrated that the age dependent increase in H2O2 production by MAOs is fully related to the expression of MAO-A. So, this study also demonstrates that during aging, MAO-A is an important regulator of cellular ROS.

Umbarkar et al (2015)43 and her colleagues investigated whether MAO-A can be a potential source of ROS and contribute to development of cardiomyopathy. For detailed examination, diabetes was induced in wistar rats by single intraperitoneal injection of streptozotocin (STZ). To investigate the role of MAO-A in the development of pathophysiological features of diabetic cardiomyopathy, hyperglycaemic and age matched control rats were treated with or without MAO-A specific inhibitor clorgyline (CLG) at 1mg/kg/day for 8 weeks. Diabetes upregulated MAO-A activity. Elevated markers of oxidative stress such as cardiac lipid peroxidation, superoxide dismutase activity uncoupling protein 3 expressions, enhanced apoptotic cell death and increased fibrosis. All these parameters were attenuated by CLG treatment indicating a positive correlation of MAO-A with all these and MAO-A -derived ROS contributes in diabetic cardiomyopathy.

So, these findings provide a skeletal structure for the most unexplored role of MAO-A in the biology i.e aging heart and associated physiological condition.

Manzella et al., in 201844 analyzed the effects of aging on MAO-A expression, oxidative stress and senescent markers in adult mouse ventricular myocytes. Upregulation of MAO-A along with 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation was observed in 20 months old mouse cardiomyocytes compared to 3 months old mouse cardiomyocytes. An increase in MAO-A enzymatic activity was noticed in old cardiomyocytes along with increase in ROS generation in response to MAO-A substrate tyramine (Tyr). On the other hand, classical senescent markers like p53, p21 and p15/p16 were significantly upregulated at protein level in aged cardiomyocytes. ROS generation induced by tyramine was prevented by either treatment with selective MAO-A inhibitor clorgyline, or siRNA mediated knockdown of MAO-A or treatment with antioxidant like trolox. Researchers also evaluated MAO-A induced DNA damage and the consequent activation of DNA damage response by comet assay over a 72h period of tyr stimulation. So, collectively they have demonstrated MAO-A activation in aging process results in oxidative stress and DNA damage response.

MAO-A activities are enhanced in several models of heart failure and aging rat hearts. For investigation of the consequences of increased MAO-A activity in heart failure and aging, Villeneuve and co-workers developed in-vitro and in-vivo model of MAO-A over expression45. In-vivo over expression of MAO-A in young mice led to decreased level of bioamines (norepinephirine and serotonin) along with increased concentration of aldehyde metabolites generated by MAO-A catalysed amine oxidation. On the other hand, mice with cardiac-selective MAO-A over expression (Tg-MAO-A) displayed enhanced level of H2O2 in heart and mitochondrial DNA. Gene expression analysis by microarray in Tg-MAO-A hearts revealed downregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) pathway involved in mitochondrial biogenesis. Subsequently, Tg-MAO-A executes progressive cardiomyocyte necrosis causing premature death by heart failure at nine months of age. In in-vitro condition, activation of p53 by MAO-A was responsible for mitochondrial damage, PGC-1α down regulation and cardiomyocyte necrosis.

The autophagy-lysosome pathway is an important mechanism of quality control in heart for damage proteins and organelles like mitochondria but its efficiency decreases gradually during aging and heart failure46,47. A recent research by Santin et al (2016)48 demonstrated that persistent activation of MAO-A led to the progressive accumulation of LC3 positive autophagosomes [Fig. 1], p62 ubiquitinylated proteins and damaged mitochondria. Blockage of autophagic flux was due to attenuated lysosomal acidification and biogenesis through inhibition of transcription factor EB (TFEB)–a master regulator of autophagy-lysosome pathway. Interestingly, in MAO-A overexpressed mice, gene therapy with cardiomyocyte driven TFEB adenoassociated vector rescued autophagic dysfunction, cardiac remodelling and heart failure. Although, changes associated with MAO-A activation, like mitochondrial damage, p53 activation, PGC-1α downregulation and autophagy blockage [Fig. 1] mimic accelerated cardiac aging detailed examination is needed to resolve this issue.


Figure 1: Model showing the role of MAO-A in cardiac pathology and heart failure. Enhanced MAO-A activity produces more H2O2 and contributes in oxidative stress and heart failure. MAO-A-generated oxidative stress triggers p53 activation leading to the downregulation of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. On the other hand, MAO-A-generated oxidative stress impairs lysosome function and acidification leading to autophagic flux blockade and altered mitochondrial quality control. This figure is basically adapted and modified from following two papers:

1. Umbarkar et al., 2015; Free Rad Biol and Medicine; 87: 263-273.

2. Villeneuve et al., 2013; Antioxidants and Redox signalling; 18: 5-18.

There are evidences regarding role of MAO-B in age related heart disease. It was recently shown that in a model of pressure overload, genetic deletion of MAO-B protects against oxidative stress, apoptosis and ventricular dysfunction16. The authors also demonstrated a direct link between MAO activation and ROS formation inside mitochondria and compared the accumulation of ROS in the mitochondrial and cytosolic compartment using a redox fluorescent probe and observed earlier increase in H2O2 level (10 min) in mitochondria compared to cytosol (30 min) after MAO activation.

Apart from ROS, aldehydes produced during metabolism of dopamine by MAO-B were recently shown to contribute in mitochondrial dysfunction in cardiac cells. In heart tissues, aldehyde dehydrogenase 2 (ALDH2) is the most abundant isoform. In-vitro knockdown of ALDH2 by siRNA treatment endorses dopamine induced accumulation of aldehydes through MAO-B and alteration in mitochondrial membrane potential39. In-vivo study proved that ALDH2 deficiency in mice contributed in cardiac aging with aldehyde overload, impaired autophagic flux. So, altogether, these studies support a role for aldehydes in cardiac aging.

The activity of MAO-A was measured in mouse and rat models of heart failure. Pulmonary hypertension is a known pathological situation to increase vascular pulmonary resistance resulting right ventricular resistance and ultimately right ventricular failure. Using a rat model of pulmonary hypertension, Liu et al (2008)49 measured the protein level expression and activity of MAO-A in the right and left ventricles. In the right ventricle, MAO-A protein level expression and activity were found to be lower than in the left ventricle. These results were associated with a lower MAO-A mRNA level in the left ventricle. Petrak et al. (2011)50 identified myocardial proteins and measured the expression of MAO-A in the myocardial tissue using a proteomic analysis. Compared with sham rats, those with HF induced by a chronic aorto-caval fistula showed an up-regulation of MAO-A levels.

A little upregulation in MAO-A activity is sufficient to trigger deleterious effects in the heart. Villeneuve et al. (2013)45 examined the consequences of MAO-A specific over expression in cardiomyocytes, obtained by a transgenic method on cardiac morphology and function in mice. The significant reduction of fractional shortening, ventricular dilation between 3 and 7 months and pulmonary congestion in the 7-month-old transgenic mice confirmed the emergence of HF. MAO up-regulation did not induce myocardial hypertrophy but it was associated with cardiomyocyte death and dilated cardiomyopathy. On the other hand, chronic administration of clorgyline- (MAO-A inhibitor) prevented left ventricular dysfunction and dilation in transgenic mice.

The impact of null MAO-A activity on heart function was studied in a murine model expressing a dominant-negative MAO-A51. These mice had preserved left ventricular pressure and cardiac volumes, but also maintained their cardiac function after 9 weeks of transverse aortic constriction (TAC). Histological examination revealed that, the dominant negative mice submitted to TAC had less interstitial fibrosis51. Thus, genetic inhibition of MAO-A activity helped limiting the consequences of pressure overload and prevented the transition from hypertrophy to failure. On the other hand, pharmacological inhibition of MAO-A by clorgyline also prevented adverse cardiac structural effects.

MAO-A substrate serotonin (5-HT) is known to play a major role in the regulation of cardiac function52. Lairez et al. found that the myocardial 5-HT was augmented in MAO-A KO mice subjected to ventricular pressure overload by aortic banding, compared to the wild-type mice53. 5-HT2A receptors of serotonin also increased in the ventricles of the MAO-A KO mice53. Their inhibition reduced left ventricular hypertrophy after aortic banding. According to these results, the regulation of peripheral 5-HT by MAO-A may play a role in ventricular remodelling, and particularly hypertrophy, through the 5-HT2A receptor. In addition, targeted MAO-A over-expression in mouse cardiomyocytes led to a significant cardiac serotonin depletion and to the rise of its metabolite 5-hydroxyindoleacetic acid (5-HIAA), due to the reaction catalyzed by MAO-A45. In conditions of pressure overload, norepinephrine (NE) catabolism is increased: the cardiac amount of the primary catabolic product of NE, dihydroxyphenyl glycol (DHPG), is elevated, whilst the level of NE is significantly reduced54. Interestingly, addition of clorgyline prevents the rise of DHPG and cardiac NE depletion54. Furthermore, NE metabolism by MAO-A is associated with exacerbated oxidative stress, hypertrophy, chamber dilation and reduced systolic function54.

The imbalance between antioxidant defense mechanism and ROS production are the main cause of oxidative stress in a physiological system. In case of cardiovascular diseases (CVD) , in the blood vessel wall layers can produce ROS in pathological conditions55. For the majority of CVDs the enzymatic sources of ROS include NAD(P)H oxidase, lipoxygenase, cyclooxygenase (COX), Xanthine oxidase (XO), uncoupled nitric oxide synthase (NOS), Cytochrome P45056. Generally, NADPH Oxidase (NOX) commonly found on cellular membrane and overexpression of NOX2 and NOX4 is commonly associated with CVDs. A study by Kuroda et al (2010)57 showed that NOX4 knockout mice showed lower level of cardiac O2- suggesting that NOX4 is a potential source of superoxide in cardiac myocytes. On the other hand, NOX4 overexpression worsened the cardiac function and induced apoptosis and fibrosis in mice with response to pressure overload57.

Cardiac aging and disease are associated with oxidative stress which can impair redox signals by altering essential cystein thiolets. Cardiac specific overexpression of catalase (Cat) an enzyme that detoxifies excess H2O2, is useful to protect from oxidative stress and endorses delayed cardiac aging in mice58. Catalase overexpression globally decreases thiol occupancy including numerous mitochondrial and contractile proteins. System Biology approach assaigned the majority of the proteins with differentially modified thiols in Cat transgenic mice (Tg) in the pathways of cardiac aging including cellular stress response, proteostasis and apoptosis. Moreover, Cat Tg mice exhibited diminished protein glutathione adducts and decreased H2O2 production from mitochondrial complex I and complex II- suggesting improved function of cardiac mitochondria. So, this research suggests that catalase may alleviate cardiac disease and aging by modulationg cystine thiol oxidation58.

Another first line of defence against mitochondrial ROS is Superoxide dismutase (SODs) which plays a role to dismutate superoxide into H2O2. Among three distinct isoforms of SODs, SOD2 specifically localizes in the mitochondrial matrix59,60. Different researchers have investigated the role of SOD2 in cardiac aging. Deletion of SOD2 gene results in early postnatal lethality in mice61,62. SOD2 deficient (SOD2+/-) mice are viable but demonstrate increased susceptibility to oxidative stress, diminished mitochondrial function and enhanced sensitivity to apoptosis63,64. On the other hand, in an atherosclerosis background [(apo E) KO], SOD2 deficiency results in accelerated atherosclerosis57, and endothelial dysfunction in mice65.

Zhou et al., 2012 have demonstrated that SOD2 deficiency over a lifetime is enough to induce aortic stiffening, decreased aortic compliance and cause cardiac dysfunction. Aortic stiffening with aging in SOD +/- mice is associated with structural changes in the aortic wall with increased collagen content and rupture in elastin laminae. SOD2 deficiency also increases collagen I and MMP2 production in aged smooth muscle cells (SMC). So, they have concluded that mitochondrial oxidative stress over a lifetime causes aortic stiffening by inducing vascular wall remodelling, SMC apoptosis66.

Recently, different research papers have revealed the importance of MAO-A as a major source of H2O2 in heart which may play an important role in the onset and progression of cardiac injury67. Moreover, it is well established that MAO-A’s expression and its ability to produce ROS increases with age42. It is also pronounced in age associated chronic disease like hypertension, pressure overload, and diabetes. MAO-A overactivity elicits mitochondrial damage and myocardial degeneration in rodent models of pressure overload and diabetes which can effectively be inhibited by using MAO-A inhibiting drugs43,45,51. This concept has become even more relevant now a days in support of well documented tissue specific increase in MAO-A levels with age. MAO-A level has shown to increase 6 fold in the aging heart- a phenomenon proposed to be specifically enhancing the effects exerted by factors and conditions that trigger the cardiac damage42. On the other hand, a clinical study has showed that there is a correlation between MAO-A levels and postoperative arterial fibrillation, a cardiac arrhythmia often associated with aging68.

Moreover, by using gene targeted approaches in mice like cardiomyocyte specific overexpression or deletion, researchers have demonstrated the deleterious role played by MAO-A in ventricular dysfunction during chronic ischemia69. Mechanistically, the excess of ROS generated by MAO-A lead to an accumulation of 4-hydroxynonenal (4-HNE) inside the mitochondria. 4-HNE is basically a product of lipid peroxidation and reactive aldehyde that is particularly deleterious as it is more long lived than ROS and forms adducts with proteins to modify their function and conformation. It was also demonstrated that activation of MAO-A and generation of H2O2 lead to cardiolipin peroxidation and accumulation of mitochondrial 4-HNE. Moreover, 4-HNE is a main contributor of MAO-A associated ventricular dysfunction69. So, overall, we can say that during heart failure, an increase in MAO-A substrates together with enhanced MAO-A expression leads to the accumulation of H2O2 into the mitochondria. Next, ROS mediated peroxidation of cardiolipin enhances the production of 4-HNE which binds to VDAC (Voltage dependent anion channel) and MCU (Mitochondrial Ca+2 uniporter). A resulting increase in Ca+2 uptake leads to Ca+2 overload and mitochondrial dysfunction with ATP depletion and loss of mitochondrial membrane potential.

The synchronization of coupled oscillators plays an important role in many biological systems like heart. In case of heart disease, cardiac myocytes can exhibit abnormal electrical oscillations such as early after depolarizations (EADs) which are associated with lethal arrhythmias. Recent experiments on isolated rabbit heart in a Langerdorff perfusion system have demonstrated the role of exogenous H2O2 at (0.2-1) mM in inducing early after depolarization and subsequent arrhythmias such as polymorphic ventricular tachycardia70 confirming previously postulated role of endogenous ROS in reperfusion arrhythmias during myocardial infarction71. Among the molecular targets of ROS several non-selective cation channels of the transient receptor potential TRP family such as TRPM2 or TRPM7 may allow late calcium inflow during ischemia leading to necrosis72. Growing evidences have suggested that Ca+2 entry through TRP channel might play a pivotal role in cardiac function and pathology. TRP proteins are divided into six groups TRPC (Canonical), TRPV (Vaniloid), TRPM (Melastatin), TRPA (Ankyrin), TRPML (Mucolipin), TRPP (Polycystin) which are activated by different physical or chemical stimuli73. A landmark study has demonstrated convincingly that activation of neuronal TRPM7 channels by peroxynitrite happens during an in-vitro model of ischemia. Here, this group have shown that antiexcitotoxic therapy (AET) in anoxic neurons unmasks a lethal cation current IOGD (OGD = Oxygen glucose deprivation) reported to mediate neuronal death. In OGD, IOGD is activated by activated recative oxygen/ N2 species (ROS) permitting Ca+2 uptake that further stimulates ROS and IOGD activation. Blocking IOGD or suppressing TRPM7 expression prevents anoxic neuronal death even in the absence of AET, indicating that TRPM7 is an important mediator of anoxic death74.

On the other hand, TRPM7 has been evidenced in isolated ventricular cardiomyocytes of different species like rat and pig75. Apart from several TRP channels, cardiac tissue can express Mg +2 inhibited, non selective cation current (IMIC) that bears many characteristics of cation current channels. Researchers have used whole cell voltage clamp technique in rat and pig ventricular myocytes to characterize the blockage and permeation property of cardiac IMIC channels. They also compared IMIC channels with TRP channels particularly with Mg+2 sensitive TRMP6 and TRMP7 channels. They observed that removing extracellular divalent cation unmasks large inward and outward monovalent current which can be inhibited by Mg+2 75. In an in-vitro model of cellular replicative senescence, higher levels of TRMP7 inward current have been recorded in human amniocytes, possibly as a result of activation of increased levels of endogenous ROS. Transient receptor potential (TRP)M7 like current density at -120mV was significantly increased in senescent amniocyte76.

MAO-A has been predominantly found in the brain and in noradrenergic and dopaminergic neurons. MAO-A has also been found in many peripheral tissues including cardiomyocytes. The role of MAO-A in terminating the actions of neurotransmitters/dietary amines in central and peripheral nervous system and in the extra neuronal tissue have been extensively studied and the oxidative deamination by MAO-A can influence the cardiac function both directly or indirectly. Serotonin (5-HT), released from the extra neuronal tissue and catecholamine like norepinephrine (NE) released from the intracardiac nerves, interact with their receptors and uptaken through the extra neuronal monoamine transporter (EMT), present in the cardiomyocyte membrane. Once in the cytoplasm, these neurotransmitters are degraded by MAO-A and generate H2O2 that affect cellular processes even in the physiological conditions. Limited information has been achieved till now about the products of its activity. H2O2 is a ROS that could be toxic at high concentrations, or it could generate hydroxyl radical in the presence of Fe2+. Ammonia accumulation and aldehyde intermediates are also toxic for the biological systems and a decrease in aldehyde dehydrogenase activity, due to increased oxidative stress can influence the system67. Formation of these by products of MAO-A activity in the cardiomyocytes can directly influence the heart.

Norepinephrine and serotonin exhibit a variety of biological responses, beyond their roles as neurotransmitters in the central nervous system. The increase in sympathetic nervous system (SNS) activity is typical of chronic heart failure (HF) and is characterized by norepinephrine spillover and decreased neuronal uptake77. Physiological aging is also characterized by SNS dysfunction as shown by the increase in circulating catecholamine levels in old compared to adult individuals78. Higher serotonin levels were also associated with worse HF symptoms and systolic dysfunction79,80. Therefore, the increase in norepinephrine and serotonin levels could participate in cardiovascular dysfunction and may explain the age-associated increase in cardiovascular morbidity and mortality81. Hence the activity of MAO-A present in the neural system shows a control mechanism to balance the supply of serotonin and norepinephrine substrate to be uptaken through the transporter present in the cardiomyocyte membrane and thereby indirectly influence the cardiac function.

Aging is a complex process where multiple factors are involved. Growing evidences have demonstrated that oxidative stress, mitochondrial dysfunction contributes in many age related diseases. CVDs are the leading causes of death in elderly person world wide. As discussed in many research articles, old age is a significant risk factor for CVDs. This aging population need to develop therapeutic strategies that prevent myocardial dysfunction in the elderly, especially LVH and diastolic dysfunction. Hypertension and old age are the most common causes of LVH, which increases the risk of coronary heart disease, congestive heart failure, stroke, and sudden death. The roles of mitochondrial ROS, insulin-IGF-PI3K, catecholamine, and nutrient signaling have been widely discussed in different research reports. Further studies are needed to elucidate the complex interactions between mitochondrial ROS, SIRTs, mTOR, Ca+2 , and other cellular signalling. As clinical trials in case of antioxidant application to attenuate the progression of CVDs have shown disappointing results82, these may not be the optimal therapeutic agents. However, there are several promising mitochondrial-targeted small molecule antioxidants, including mitochondrial-targeted ubiquinone (MitoQ), and SS31 peptide antioxidants83-85. Other mitochondrial targeted mechanisms, such as cyclosporine to block the opening of mitochondrial permeability-transition pore86, are also attractive treatment strategies. Further clinical trials are necessary to study the potential application of mitochondrial targeted therapeutics in the treatment or prevention of cardiac aging, hypertensive cardiomyopathy, and heart failure.

In the past few years, researchers have uncovered that MAO’s activation and ROS generation can drive mitochondrial damage and age related diseases. Since the p53/PGC-1α mitochondrial dysfunction axis has been identified as a major pathway involved in postmitotic senescence, MAO-A may constitute an important factor during cardiac aging and heart failure and it could serve as a target for drugs employing cardioprotective actions. Moreover, apart from H2O2 formation, MAOs are also a source of reactive aldehydes and ammonia. Stimulation of mitochondrial ALDH2 activity, the enzyme responsible for aldehyde conversion into the corresponding carboxylic acids, improves mitochondrial function and reduces cardiac damage in several models of cardiac injury. Evidence available so far suggests that MAO inhibition is beneficial for treatment of cardiovascular pathologies. From a translational point of view a major hurdle is accepting the use of MAO inhibitors in the clinic. In fact, consumption of food rich in tyramine, such as wine and cheese, has been found to cause hypertensive crises in patients treated with irreversible MAO-A inhibitors. So, the probable solution of this problem is the introduction of a new generation of reversible MAO inhibitors, which appears to prevent this adverse effect. MAO-A inhibition is protective in the setting of different cardiac stresses such as pressure overload HF, diabetic cardiomyopathy, chronic ischemia, indicating its pivotal role in deleterious ROS production and mitochondrial dysfunction67,69. In a therapeutic point of view, researchers have found that the administration of moclobemide, a MAO-A selective and reversible inhibitor, which is the active compound of moclamine drug, widely used as an antidepressant, prevented cardiac dysfunction, lung congestion and ventricular remodeling in mice with chronic cardiac ischemia87. It would be interesting to consider the possibility of repurposing this drug for heart therapy in the future. Further studies will be required to provide more clear understanding of the role of MAO-A in the molecular mechanisms linking biogenic amine metabolism and ROS generation to accelerate disease progression in aging process. A better understanding of response to oxidative stress and mitochondrial dynamics and MAO-A regulation will lead to new therapeutic approaches for the prevention of age associated cardiac diseases.

The authors declare that they have no conflict of interest with the contents of this article.

The authors would like to acknowledge all the lab members for their support during the preparation of this manuscript and finally acknowledge the Department of Biotechnology, NIT Durgapur for extending facilities for research work in the related field.

  1. Levy ER, Powell JF, Buckle VJ, et al. Localization of monoamine oxidase A gene to XP 11.23-11.4 by in situ hybridization: implication for Norrie disease. Genomics. 1989; 5: 368-370.
  2. Shih JC, Chen K, Ridd MJ. Monoamine oxidase: from genes to behaviour. Annu Rev Neurosci. 1999; 22:197-217.
  3. Scrutton NS. Chemical aspects of amine oxidation by flavoprotein enzymes. Nat Prod Rep. 2004; 21: 722-730.
  4. Singer TP, Ramsay RR. Flavoprotein structure and mechanism 2. Monoamine oxidases: old friends hold many surprises. FASEB J. 1995; 9: 605-610.
  5. Wang CC, Borchert A, Ugun-Klusek A, et al. Monoamine oxidase A expression is vital for embryonic brain development by modulating developmental apoptosis. J Biol Chem. 2011; 286: 28322-28330.
  6. Wouters J. Structural aspects of monoamine oxidase and its reversible inhibition. Curr Med Chem. 1998; 5: 137-162.
  7. Biswas P, Dhabal S, Das P, et al. Role of monoamine oxidase a (MAO-A) in cancer progression and metastasis. Cancer cell & Microenv. 2018; 5: e1623.
  8. Cathcart MK, Bhattacharjee A. Monoamine oxidase A (MAO-A): a signature marker of alternatively activated monocytes/macrophages. Inflamm Cell Signal. 2014; 1: 152-159.
  9. Dhabal S, Das P, Biswas P, et al. Regulation of monoamine oxidase A (MAO-A) expression, activity and function in IL-13-stimulated monocytes and A549 lung carcinoma cells. J Biol Chem. 2018; RA 118.02321.
  10. Wu JB, Shao C, Li X, et al. Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. J Clin Invest. 2014; 124: 2891-2908.
  11. Bhattacharjee A, Shukla M, Yakubenko VP, et al. IL-4 and IL-13 employ discrete signaling pathways for target gene expression in alternatively activated monocytes/macrophages. Free Radic Biol Med.2013; 54: 1–16.
  12. Bianchi P, Kunduzova O, Masini E, et al. Oxidative stress by monoamine oxidase mediates receptor-independent cardiomyocyte apoptosis by serotonin and postischemic myocardial injury. Circulation. 2005; 112: 3297-3305.
  13. Flatt T. A new definition of aging? Front Genet.2012; 3: 148.
  14. Pchejetski D, Kunduzova O, Dayon A, et al. Oxidative stress-dependent sphingosine kinase-1 inhibition mediates monoamine oxidase A-associated cardiac cell apoptosis. Circ Res. 2007; 100: 41-49.
  15. Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998; 78(2): 547–581.
  16. Sohal RS. The free radical hypothesis of aging an appraisal of the current status. Aging Milano. 1993; 5: 3-17.
  17. Wickens AP. Aging and the free radical theory. Respir Physiol. 2001; 128: 379-391.
  18. Granger DN. Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 1988; 255: H1269–H1275.
  19. Babior BM. NADPH oxidase: an update. Blood. 1999; 93: 1464–1476.
  20. Lenaz G, Bovina C, D’Aurelio M, et al. Role of mitochondria in oxidative stress and aging. Ann NY Acad Sci. 2002; 959: 199–213.
  21. Lenaz G. The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology. IUBMB Life. 2001; 52: 159–164.
  22. Liu Y, Fiskum G, Schubert D. Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem. 2002; 80: 780–787.
  23. Weyler W, Hsu YP, Breakefield XO. Biochemistry and genetics of monoamine oxidase. Pharmacol Ther. 1990; 47: 391–417.
  24. Vindis C, Seguelas MH, Bianchi P, et al. Monoamine oxidase B induces ERK-dependent cell mitogenesis by hydrogen peroxide generation. Biochem Biophys Res Commun. 2000; 271: 181–185.
  25. Vindis C, Seguelas MH, Lanier S, et al. Dopamine induces ERK activation in renal epithelial cells through H2O2 produced by monoamine oxidase. Kidney Int. 2001; 59: 76–86.
  26. Monti D, Troiano L, Tropea F, et al. Apoptosis–programmed cell death: a role in the aging process? Am J Clin Nutr. 1992; 55: 1208S–1214S.
  27. Sauer H, Wartenberg M, Hescheler J. Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell Physiol Biochem. 2001; 11: 173–186.
  28. Von Wangenheim KH, Peterson HP. Control of cell proliferation by progress in differentiation: clues to mechanisms of aging, cancer causation and therapy. J Theor Biol. 1998; 193: 663–678.
  29. Fowler JS, Volkow ND, Wang GJ, et al. Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiol Aging. 1997; 18: 431–435.
  30. Mahy N, Andres N, Andrade C, et al. Age-related changes of MAO-A and -B distribution in human and mouse brain. Neurobiology Bp. 2000; 8: 47–54.
  31. Strolin Benedetti M, Dostert P. Monoamine oxidase, brain aging and degenerative diseases. Biochem Pharmacol. 1989; 38: 555–561.
  32. Anversa P, Hiler B, Ricci R, et al. Myocyte cell loss and myocyte hypertrophy in the aging rat heart. J Am Coll Cardiol. 1986; 8: 1441–1448.
  33. Anversa P, Palackal T, Sonnenblick EH, et al. Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res. 1990; 67: 871–885.
  34. Olivetti G, Giordano G, Corradi D, et al. Gender differences and aging: effects on the human heart. J Am Coll Cardiol. 1995;26: 1068– 1079.
  35. Olivetti G, Melissari M, Capasso JM, et al. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res. 1991; 68: 1560–1568.
  36. Pimentel DR, Amin JK, Xiao L, et al. Reactive oxygen species mediate amplitude-dependent hypertrophic and apoptotic responses to mechanical stretch in cardiac myocytes. Circ Res. 2001; 89: 453–460.
  37. Sawyer DB, Siwik DA, Xiao L, et al. Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol. 2002; 34: 379–388.
  38. Abete P, Napoli C, Santoro G, et al. Age-related decrease in cardiac tolerance to oxidative stress. J Mol Cell Cardiol. 1999; 31: 227–236.
  39. Kaludercic N, Mialet-Perez J, Paolocci N, et al. Monoamine oxidases as sources of oxidants in the heart. J Mol Cell Cardiology. 2014; 34–42.
  40. Sivasubramaniam SD, Finch CC, Rodriguez MJ, et al. A comparative study of the expression of monoamine oxidase-A and -B mRNA and protein in non- CNS human tissues.Cell and Tissue Research. 2003; 313(3): 291–300.
  41. Youdim MB, Bakhle YS. Monoamine oxidase: isoforms and inhibitors in Parkinson's disease and depressive illness. Br J Pharmacol. 2006; 147 (Suppl 1): S287 S296.
  42. Maurel A, Hernandez C, Kunduzova O, et al. Age-dependent increase in hydrogen peroxide production by cardiac monoamine oxidase A in rats. Am J Physiol Heart Circ Physiol. 2003; 284: H1460–H1467.
  43. Umbarkar P, Singh S, Arkat S, et al. Monoamine oxidase-A is an important source of oxidative stress and promotes cardiac dysfunction, apoptosis and fibrosis in diabetic crdiomyopathy. Free Rad Biol and Medicine. 2015; 87: 263-273.
  44. Manzella N, Satin Y, Maggiorani D, et al. Monoamine oxidase A is a novel driver of strss induced premature senescence through inhibition of parkin-mediated mitophagy. Aging Cell. 2018; e12811.
  45. Villeneuve C, Guilbeau-Frugier CL, Sicard P, et al. p53-PGC-1a Pathway Mediates Oxidative Mitochondrial Damage and Cardiomyocyte Necrosis Induced by Monoamine Oxidase-A Upregulation: Role in Chronic Left Ventricular Dysfunction in Mice. Antioxidants and Redox signalling. 2013; 18 (1): 5-18.
  46. Marzetti E, Csiszar A, Dutta D, et al. Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics. American Journal of Physiology Heart and Circulatory Physiology. 2013; 305(4): H459–H476.
  47. Orogo AM, Gustafsson AB. Therapeutic targeting of autophagy: potential and concerns in treating cardiovascular disease. Circulation Research. 2015; 116(3): 489–503.
  48. Santin Y, Sicard P,Vigneron F, et al. Oxidative stress by monoamine oxidase-A impairs transcription factor EB activation and autophagosome clearance, leading to cardiomyocyte necrosis and heart failure. Antioxid Redox Signal. 2016; 25: 10-27.
  49. Liu L, Marcocci L, Wong CM, et al. Serotonin-mediated protein carbonylation in the right heart Free Radic. Biol Med. 2008; 45: 847–854.
  50. Petrak J, Pospisilova J, Sedinova M, et al. Proteomic and transcriptomic analysis of heart failure due to volume overload in a rat aorto-caval fistula model provides support for new potential therapeutic targets — monoamine oxidase A and transglutaminase 2, Proteome Sci. 2011; 9 : 69.
  51. Kaludercic N, Takimoto E, Nagayama T, et al. Monoamine oxidase A-mediated enhanced catabolism of norepinephrine contributes to adverse remodeling and pump failure in hearts with pressure overload, Circ Res. 2010; 106: 193–202.
  52. Bianchi P, Kunduzova O, Masini E, et al. Oxidative stress by monoamine oxidase mediates receptor-independent cardiomyocyte apoptosis by serotonin and postischemic myocardial injury. Circulation. 2005; 112: 3297-3305.
  53. Lairez O, Calise D, Bianchi P, et al. Genetic deletion of MAO-A promotes serotonin-dependent ventricular hypertrophy by pressure overload. J Mol Cell Cardiol. 2009; 46: 587–595.
  54. Kaludercic N, Carpi A, Menabo R, et al. Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury. Biochim Biophys Acta 2011; 1813: 1323-1332.
  55. Reid MB. Redox modulation of skeletal muscle contraction: what we know and what we don’t. J Applied Physiol. 2001; 90: 724-731.
  56. Bedard K, Krause KH. The NOX family of ROS generating NADPH oxidases physiology and pathophysiology. Physiol Rev. 2007; 87: 245-313.
  57. Kuroda J, Ago T, Matsushima S, et al. NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart, Proceedings of the National Academy of Sciences of the United States of America. 2010; 35: 15565-15570.
  58. Yao C, Behring JB, Shao D, et al. Overexpression of catalase diminishes oxidative cysteine modifications of cardiac proteins. PLoS ONE. 2015; 10: e0144025.
  59. Suzuki Y, Ali M, Fischer M, et al. Human copper chaperone for superoxide dismutase 1 mediates its own oxidation-dependent import into mitochondria. Nat Commun. 2013; 4: 2430.
  60. Kawamata H, Manfredi G. Import, maturation, and function of SOD1 and its copper chaperone CCS in the mitochondrial intermembrane space. Antioxid. Redox Signal. 2010; 13: 1375–1384.
  61. Bleier L, Drose S. Superoxide generation by complex III: from mechanistic rationales to functional consequences. Biochim Biophys Acta 2013; 1827: 1320–1331.
  62. Turrens JF, Alexandre A, Lehninger AL. Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria. Arch. Biochem. Biophys. 1985; 237: 408–414.
  63. Orsini F, Migliaccio E, Moroni M, et al. The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential. J. Biol. Chem. 2004; 279: 25689–25695.
  64. Giorgio M, Migliaccio E, Orsini F, et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell. 2005; 122: 221–233.
  65. Block K, Gorin Y, Abboud HE. Subcellular localization of NOX4 and regulation in diabetes. Proc Natl Acad Sci USA. 2009; 106: 14385–14390.
  66. Zhou RH, Vendrov AE, Tchivilev I, et al. Mitochondrial Oxidative Stress in Aortic Stiffening With Age: The Role of Smooth Muscle Cell Function. Arterioscler Thromb Vasc Biol. 2012; 32: 745–755.
  67. Kaludercic N, Mialet-Perez J, Paolocci J, et al. Monoamine oxidases as sources of oxidants in the heart. Journal of Molecular and Cellular Cardiology. 2014; 73: 34–42.
  68. Anderson EJ, Efird JT, Davies SW, et al. Monoamine oxidase is a major determinant of redox balance in human atrial myocardium and is associated with postoperative atrial fibrillation. Journal of the American Heart Association. 2014; 3: e000713.
  69. Santin Y, Fazal L, Sainte-Marie Y, postischemic cardiac remodeling. Cell Death Differ 2019.
  70. Satoa D, Xie LH, Sovaria AA, et al. Synchronization of chaotic early after depolarizations in the genesis of cardiac arrhythmias. Proc Natl Acad Sci U S A. 2009; 106: 2983-2988.
  71. Amuzescu B, Istrate B, Mubagwa K. Impact of Cellular Mechanisms of Ischemia on CABG Failure, in Coronary Graft Failure: State of the Art. IC Tintoiu et al. (eds.); Springer 2016. DOI 10.1007/978-3-319-26515-5_31.
  72. Clapham DE. TRP channels as cellular sensors. Nature. 2003; 426: 517-524.
  73. Falcón D, Otero IG, Calderón-Sánchez E, et al. TRP Channels: Current Perspectives in the Adverse Cardiac Remodeling. Front Physiol. 2019. doi: 10.3389/fphys.2019.00159.
  74. Aarts M, Iihara K, Wei WL, et al. A key role for TRPM7 channels in anoxic neuronal death. Cell. 2003; 115: 863-877.
  75. Gwanyanya A, Amuzescu B, Zakharov SI, et al. Magnesium-inhibited, TRPM6/7-like channel in cardiac myocytes: permeation of divalent cations and pH-mediated regulation. J Physiol. 2004; 15: 761-776.
  76. Airini R, Iordache F, Alexandru D, et al. Senescence-induced immunophenotype, gene expression and electrophysiology changes in human amniocytes. J Cell Mol Med. 2019; 23: 7233-7245.
  77. Floras JS. Sympathetic nervous system activation in human heart failure: clinical implications of an updated model. J American Col Cardiol. 2009; 54: 375–385.
  78. Esler MD, Turner AG, Kaye DM, et al. Aging effects on human sympathetic neuronal function. The American J Physiol. 1995; 268: R278– R285.
  79. Nigmatullina RR, Kirillova VV, Jourjikiya RK, et al. Disrupted serotonergic and sympathoadrenal systems in patients with chronic heart failure may serve as new therapeutic targets and novel biomarkers to assess severity, progression and response to treatment. Cardiology. 2009; 113: 277–286.
  80. Selim AM, Sarswat N, Kelesidis I, et al. Plasma serotonin in heart failure: possible marker and potential treatment target. Heart Lung Circulation. 26: 442–449.
  81. Rich MW. Heart failure in the 21st century: a cardiogeriatric syndrome. The J of Gerontol. 2001; 56: M88–M96.
  82. Steinhubl SR. Why have antioxidants failed in clinical trials? Am J Cardiol. 2008; 101: 14D–19D.
  83. Adlam VJ, Harrison JC, Porteous CM, et al. Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J. 2005; 19: 1088–1095.
  84. Anderson EJ, Lustig ME, Boyle KE, et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest. 2009; 119: 573–581.
  85. van Empel VP, Bertrand AT, van Oort RJ, et al. EUK-8, a superoxide dismutase and catalase mimetic, reduces cardiac oxidative stress and ameliorates pressure overload-induced heart failure in the harlequin mouse mutant. J Am Coll Cardiol. 2006; 48: 824–832.
  86. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med. 2008; 359: 473–481.
  87. van Haelst IM, van Klei WA, Doodeman HJ, et al. Antidepressive treatment with monoamine oxidase inhibitors and the occurrence of intraoperative hemodynamic events: a retrospective observational cohort study. J Clin Psychiatry. 2012; 73: 1103–1109.

Article Info

Article Notes

  • Published on: April 21, 2020


  • Monoamine Oxidase A

  • Oxidative stress
  • Cardiac Aging
  • Cardiomyocytes
  • Heart failure
  • Reactive oxygen Species


*Dr. Ashish Bhattacharjee
Department of Biotechnology, National Institute of Technology, Durgapur-713209, West Bengal, India; Telephone No: +91-343-2754036