Metabolic therapy: cardioprotective effects of orotic acid and its derivatives

Metabolic therapy involves the administration of a substance normally found in the human body to enhance cellular reactions involved in the pathogenesis of disease. Myocardial ischaemia/reperfusion injury represents a leading cause of morbidity and mortality, also in cardiovascular disease. Therapeutic strategies aimed at limiting cardiomyocyte death during the postischaemic reperfusion and in the perioperative settings are nowadays extensively studied. Conceived originally as a dietary constituent (known as vitamin B13) only, it is now apparent that most orotic acid is synthesized in the human body where it arises as an intermediate in the biosynthetic pathway of pyrimidine nucleotides. Previous investigations in the heart suggest that orotate and its derivatives could be of significant clinical benefit in the treatment of heart disease. The present brief review is concerned with the current knowledge of the major effects of these compounds in both experimental and clinical cardiology. The potential mechanisms and biochemical pathways responsible for cardioprotection are highlighted.Biomedical Reviews 2010; 21: 47-55

CONTRIBUTION OF MONOAMINE OXIDASES TO VASCULAR OXIDATIVE STRESS IN PATIENTS WITH END-STAGE RENAL DISEASE REQUIRING HEMODIALYSIS

Arteriovenous fistula (AVF) is the 'life line' for patients with end-stage renal disease (ESRD) undergoing hemodialysis. AVF maturation failure is a poorly understood process, one of the contributors being endothelial dysfunction due to oxidative stress. Monoamine oxidases (MAOs) A and B were recently identified as novel sources of vascular oxidative stress. The aim of the present study was to assess the contribution of MAOs to the endothelial dysfunction in patients with ESDR with indication of hemodialysis. Fragments of brachial artery collaterals were harvested from ESRD patients during the surgical procedure aimed at creating the vascular access in the cubital fossa. The effect of increasing concentrations (10, 30, 100 Âľmol/L) of the irreversible MAO-A inhibitor, clorgyline and MAO-B inhibitor, selegyline, respectively on endothelial-dependent relaxation (EDR) in response to cumulative doses of acetylcholine was studied in isolated phenylephrine-preconstricted vascular rings. Hydrogen peroxide (H2O2) production was assessed using ferrous oxidation xylenol orange assay. We showed that incubation of brachial rings with MAO inhibitors significantly improved EDR and attenuated H2O2 generation in patients with ESRD. MAO-related oxidative stress might contribute to the primary dysfunction/non-maturation of the AV fistula and MAO inhibitors could improve maturation and long-term patency of the vascular access in dialysis patients.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

The Role of Mitochondrial Reactive Oxygen Species in Cardiovascular Injury and Protective Strategies

Ischaemia/reperfusion (I/R) injury of the heart represents a major health burden mainly associated with acute coronary syndromes. While timely coronary reperfusion has become the established routine therapy in patients with ST-elevation myocardial infarction, the restoration of blood flow into the previously ischaemic area is always accompanied by myocardial injury. The central mechanism involved in this phenomenon is represented by the excessive generation of reactive oxygen species (ROS). Besides their harmful role when highly generated during early reperfusion, minimal ROS formation during ischaemia and/or at reperfusion is critical for the redox signaling of cardioprotection. In the past decades, mitochondria have emerged as the major source of ROS as well as a critical target for cardioprotective strategies at reperfusion. Mitochondria dysfunction associated with I/R myocardial injury is further described and ultimately analyzed with respect to its role as source of both deleterious and beneficial ROS. Furthermore, the contribution of ROS in the highly investigated field of conditioning strategies is analyzed. In the end, the vascular sources of mitochondria-derived ROS are briefly reviewed

The Role of Mitochondrial Reactive Oxygen Species in Cardiovascular Injury and Protective Strategies

Ischaemia/reperfusion (I/R) injury of the heart represents a major health burden mainly associated with acute coronary syndromes. While timely coronary reperfusion has become the established routine therapy in patients with ST-elevation myocardial infarction, the restoration of blood flow into the previously ischaemic area is always accompanied by myocardial injury. The central mechanism involved in this phenomenon is represented by the excessive generation of reactive oxygen species (ROS). Besides their harmful role when highly generated during early reperfusion, minimal ROS formation during ischaemia and/or at reperfusion is critical for the redox signaling of cardioprotection. In the past decades, mitochondria have emerged as the major source of ROS as well as a critical target for cardioprotective strategies at reperfusion. Mitochondria dysfunction associated with I/R myocardial injury is further described and ultimately analyzed with respect to its role as source of both deleterious and beneficial ROS. Furthermore, the contribution of ROS in the highly investigated field of conditioning strategies is analyzed. In the end, the vascular sources of mitochondria-derived ROS are briefly reviewed

Monoamine oxidases are novel sources of cardiovascular oxidative stress in experimental diabetes

Diabetes mellitus (DM) is widely recognized as the most severe metabolic disease associated with increased cardiovascular morbidity and mortality. The generation of reactive oxygen species (ROS) is a major event causally linked to the development of cardiovascular complications throughout the evolution of DM. Recently, monoamine oxidases (MAOs) at the outer mitochondrial membrane, with 2 isoforms, MAO-A and MAO-B, have emerged as novel sources of constant hydrogen peroxide (H2O2) production in the cardiovascular system via the oxidative deamination of biogenic amines and neurotransmitters. Whether MAOs are mediators of endothelial dysfunction in DM is unknown, and so we studied this in a streptozotocin-induced rat model of diabetes. MAO expression (mRNA and protein) was increased in both arterial samples and hearts isolated from the diabetic animals. Also, H2O2 production (ferrous oxidation - xylenol orange assay) in aortic samples was significantly increased, together with an impairment of endothelium-dependent relaxation (organ-bath studies). MAO inhibitors (clorgyline and selegiline) attenuated ROS production by 50% and partially normalized the endothelium-dependent relaxation in diseased vessels. In conclusion, MAOs, in particular the MAO-B isoform, are induced in aortas and hearts in the streptozotocin-induced diabetic rat model and contribute, via the generation of H2O2, to the endothelial dysfunction associated with experimental diabetes

MONOAMINE OXIDASE IS A SOURCE OF OXIDATIVE STRESS IN OBESE PATIENTS WITH CHRONIC INFLAMMATION

Obesity is an important preventable risk factor for morbidity and mortality from cardiometabolic disease. Oxidative stress (including in visceral adipose tissue) and chronic low-grade inflammation are the major underlying pathomechanisms. Monoamine oxidase (MAO) has recently emerged as an important source of cardiovascular oxidative stress. The present study was purported to evaluate the role of MAO as contributor to reactive oxygen species (ROS) production in white adipose tissue and vessels harvested from patients undergoing elective abdominal surgery. To this aim, visceral adipose tissue and mesenteric artery branches were isolated from obese patients with chronic inflammation and used for organ bath, ROS production, qRT-PCR and immune-histology (IH) studies. The human visceral adipose tissue and mesenteric artery branches contain mainly the MAO-A isoform, as shown by the qRT-PCR and IH experiments. A significant up-regulation of MAO-A, the impairment in vascular reactivity and increase in ROS production were found in obese vs non-obese patients. Incubation of the adipose tissue samples and vascular rings with the MAO-A inhibitor (clorgyline, 30 min) improved vascular reactivity and decreased ROS generation. In conclusion, MAO-A is the predominat isoform in human abdominal adipose and vascular tissues, is overexpressed in the setting of inflammation, and contribute to the endothelial dysfunctionThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Monoamine Oxidase-Related Vascular Oxidative Stress in Diseases Associated with Inflammatory Burden

Monoamine oxidases (MAO) with 2 isoforms, A and B, located at the outer mitochondrial membrane are flavoenzyme membranes with a major role in the metabolism of monoaminergic neurotransmitters and biogenic amines in the central nervous system and peripheral tissues, respectively. In the process of oxidative deamination, aldehydes, hydrogen peroxide, and ammonia are constantly generated as potential deleterious by-products. While being systematically studied for decades as sources of reactive oxygen species in brain diseases, compelling evidence nowadays supports the role of MAO-related oxidative stress in cardiovascular and metabolic pathologies. Indeed, oxidative stress and chronic inflammation are the most common pathomechanisms of the main noncommunicable diseases of our century. MAO inhibition with the new generation of reversible and selective drugs has recently emerged as a pharmacological strategy aimed at mitigating both processes. The aim of this minireview is to summarize available information regarding the contribution of MAO to the vascular oxidative stress and endothelial dysfunction in hypertension, metabolic disorders, and chronic kidney disease, all conditions associated with increased inflammatory burden

METHYLENE BLUE IMPROVES MITOCHONDRIAL RESPIRATION AND DECREASES OXIDATIVE STRESS IN A SUBSTRATE-DEPENDENT MANNER IN DIABETIC RAT HEARTS

Diabetic cardiomyopathy has been systematically associated with compromised mitochondrial energetics and increased generation of reactive oxygen species (ROS) that underlie its progression to heart failure. Methylene blue is a redox-drug with reported protective effects mainly on brain mitochondria. The present study was purported to characterize the effects of acute administration of methylene blue on mitochondrial respiration, H2O2 production, and calcium sensitivity in rat heart mitochondria isolated from healthy and 2 months (streptozotocin-induced) diabetic rats. Mitochondrial respiratory function was assessed by high-resolution respirometry. Hydrogen peroxide production and calcium retention capacity were measured spectrofluorimetrically. The addition of methylene blue (0.1 ÎźM) elicited an increase in oxygen consumption of mitochondria energized with complex I and II substrates in both normal and diseased mitochondria. Interestingly, methylene blue elicited a significant increase in H2O2 release in the presence of CI substrates (glutamate-malate), but had an opposite effect in mitochondria energized with CII substrate (succinate). No changes in the calcium retention capacity of healthy or diabetic mitochondria were found in the presence of methylene blue. In conclusion, in cardiac mitochondria isolated from diabetic and non-diabetic rat hearts, methylene blue improved respiratory function and elicited a dichotomic, substrate-dependent effect on ROS production.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues

A substantial body of evidence indicates that pharmacological activation of mitochondrial ATP-sensitive potassium channels (mKATP) in the heart is protective in conditions associated with ischemia/reperfusion injury. Several mechanisms have been postulated to be responsible for cardioprotection, including the modulation of mitochondrial respiratory function. The aim of the present study was to characterize the dose-dependent effects of novel synthetic benzopyran analogues, derived from a BMS-191095, a selective mKATP opener, on mitochondrial respiration and reactive oxygen species (ROS) production in isolated rat heart mitochondria. Mitochondrial respiratory function was assessed by high-resolution respirometry, and H2O2 production was measured by the Amplex Red fluorescence assay. Four compounds, namely KL-1487, KL-1492, KL-1495, and KL-1507, applied in increasing concentrations (50, 75, 100, and 150 mumol/L, respectively) were investigated. When added in the last two concentrations, all compounds significantly increased State 2 and 4 respiratory rates, an effect that was not abolished by 5-hydroxydecanoate (5-HD, 100 mumol/L), the classic mKATP inhibitor. The highest concentration also elicited an important decrease of the oxidative phosphorylation in a K+ independent manner. Both concentrations of 100 and 150 mumol/L for KL-1487, KL-1492, and KL-1495, and the concentration of 150 mumol/L for KL-1507, respectively, mitigated the mitochondrial H2O2 release. In isolated rat heart mitochondria, the novel benzopyran analogues act as protonophoric uncouplers of oxidative phosphorylation and decrease the generation of reactive oxygen species in a dose-dependent manner