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Abstracts by Adriana V Treuer

Category: 1. Myocardial Ischemia/Infarction-Basic Session-Poster Board Number:

Journal of the American College of Cardiology, 2010

Category: Myocardial Function/Heart Failure---Basic/Molecular Background: Diastolic calcium (Ca) ... more Category: Myocardial Function/Heart Failure---Basic/Molecular Background: Diastolic calcium (Ca) leak is observed in heart failure. Cardiomyocytes from Nitric Oxide Synthase-1-defcient (NOS1 KO) mice exhibit increased sarcoplasmic reticulum (SR) Ca leak. On the other hand, nitrates in combination with hydralazine are currently used in heart failure treatment in African-American patients. Although their action as vasodilators of both nitric oxide and hydralazine are well known, their complementary effects on the myocardium remain obscure. We hypothesize that hydralazine-nitroglycerin combination is able to modulate the sarcoplasmic calcium channel ryanodine receptor (RyR2).

Journal of Cardiac Failure, 2010

Cardiomyopathy in the setting of coronary artery disease (ischemic cardiomyopathy) is the major c... more Cardiomyopathy in the setting of coronary artery disease (ischemic cardiomyopathy) is the major cause of heart failure in the developed world and a significant cause of morbidity and mortality. The degree of left ventricular dysfunction in this setting is often out of proportion to the amount of overtly infarcted tissue. Moreover, how decreased delivery of oxygen and nutrients leads to impaired contractility remains incompletely understood. The PHD prolyl hydroxylases are oxygen-sensitive enzymes that transduce changes in oxygen availability into changes in the stability and activity of the HIF transcription factor, a master regulator of genes that promote survival in a low oxygen-environment. We found that cardiac-specific PHD inactivation in mice causes ultrastructural, histological, and functional changes reminiscent of ischemic cardiomyopathy over time. Moreover, chronic expression of a stabilized HIFa variant in cardiomyocytes also led to dilated cardiomyopathy. In addition, we show that HIFa is upregulated in a murine model for ischemic cardiomyopathy, as well as samples of patients with chronic ischemia and cardiomyopathy. Together, our data establish that chronic PHD inactivation, and consequent HIF activation, plays a causal role in the pathogenesis of ischemic cardiomyopathy.

Circulation, Nov 3, 2009

Background Accumulating data support a cardioprotective role for the growth hormone (GH) axis. In... more Background Accumulating data support a cardioprotective role for the growth hormone (GH) axis. In addition, to GH itself and IGF-1, GH releasing peptides also exert a cardiac effect and GHRH mRNA is present in the heart. In order to test the hypothesis that GHRH exerts important cardioprotection we administered a potent GHRH agonist (JI-38) to rats following MI.

Circulation, Nov 25, 2014

Introduction: Dystrophic cardiomyopathy is the cardiac manifestation of Duchenne muscular dystrop... more Introduction: Dystrophic cardiomyopathy is the cardiac manifestation of Duchenne muscular dystrophy. Hearts from the mdx mouse, the mouse model of this disease, exhibit increased oxidative stress due to the up-regulation of NADPH oxidase. Abstract 16412: Altered Nitroso/Redox Balance in Dystrophic Cardiomyopathy is Associated With NOS1 Uncoupling | Circulation Página 2 de 4 http://circ.ahajournals.org/content/130/Suppl_2/A16412.short Conclusions: These results suggest that NOX2-derived oxidative stress results in H4B oxidation, causing NOS1 uncoupling. Diminished NOS1 activity has functional implications for mdx cardiomyocyte performance.

Circulation, Nov 22, 2011

Background Recently it has been appreciated that the heart harbors GHRH-receptors (GHRHR). Based ... more Background Recently it has been appreciated that the heart harbors GHRH-receptors (GHRHR). Based upon our previous report that potent GHRH agonists are cardioprotective in cardiac injury due to myocardial infarction (MI), we tested the hypothesis that reverse remodeling due to GHRH agonists are clearly receptor dependent by employing a highly selective GHRH-antagonist (MIA-602).

Circulation, Nov 22, 2011

Background. Dystrophic cardiomyopathy is the cardiac manifestation of three closely related disea... more Background. Dystrophic cardiomyopathy is the cardiac manifestation of three closely related diseases that include Duchenne and Becker muscular dystrophies, and X-linked dilated cardiomyopathy. Oxidative stress is characteristic of cardiomyopathies. Intracellular calcium ([Ca ] ) handling is abnormal in the heart of the mdx mouse, a model of Duchenne 2+ i

Short Communication by Adriana V Treuer

The Journal of Physiology, 2009

Papers by Adriana V Treuer

Diabetes mellitus is one of the most common chronic diseases worldwide. Diabetic cardiomyopathy (... more Diabetes mellitus is one of the most common chronic diseases worldwide. Diabetic cardiomyopathy (DM) is the deterioration of the myocardial function and morphology produced by the altered glucose metabolism imposed in diabetes. This process of cardiac deterioration involves the generation of oxidative species. In the diabetic heart, several sources contribute to the observed oxidative stress, such as xanthine oxidore‐ ductase (XOR), nicotinamide adenine dinucleotide phosphate (NADPH), nitrogen oxidases (NOX), mitochondria, and uncoupled nitric oxide synthases (NOS). A direct consequence of the increased production of reactive oxygen species (ROS) is NOS uncoupling. This is the aftermath of the oxidation of tetrahydrobioterin (BH4), an essential cofactor for NOS activity. When NOS is uncoupled, its activity is redirected toward the production of superoxide, instead of nitric oxide (NO), further contributing to the oxidative process. This nitroso‐redox disarrangement has a direct impa...

Circulation, 2011

Mdx mice (19 months old, n= 35) and background controls mice (C57BL/10SnJ, n=45) were used for th... more Mdx mice (19 months old, n= 35) and background controls mice (C57BL/10SnJ, n=45) were used for the study. To assess superoxide production, isolated cardiac myocytes from wild type and mdx myocytes were loaded with 2′,7′-dichlorofluorescein diacetate (DCF), and treated with vehicle (DMSO) or the NOX inhibitors apocynin (100 μmol/L) or VAS2870 (20 μmol/L) (60 cells each group, from 4 hearts) and visualized using confocal microscopy. Contractility, assessed as sarcomere shortening and calcium was evaluated using fura-2 (2). NOX2 expression was evaluated by Western Blotting.

Whereas cardiac-derived c-kit ؉ stem cells (CSCs) and bone marrow-derived mesenchymal stem cells ... more Whereas cardiac-derived c-kit ؉ stem cells (CSCs) and bone marrow-derived mesenchymal stem cells (MSCs) are undergoing clinical trials testing safety and efficacy as a cell-based therapy, the relative therapeutic and biologic efficacy of these two cell types is unknown. We hypothesized that human CSCs have greater ability than MSCs to engraft, differentiate, and improve cardiac function. We compared intramyocardial injection of human fetal CSCs (36,000) with two doses of adult MSCs (36,000 and 1,000,000) or control (phosphate buffered saline) in nonobese diabetic/severe combined immune deficiency mice after coronary artery ligation. The myocardial infarction-induced enlargement in left ventricular chamber dimensions was ameliorated by CSCs (p < .05 for diastolic and systolic volumes), as was the decline in ejection fraction (EF; p < .05). Whereas 1 ؋ 10 6 MSCs partially ameliorated ventricular remodeling and improved EF to a similar degree as CSCs, 36,000 MSCs did not influence chamber architecture or function. All cell therapies improved myocardial contractility, but CSCs preferentially reduced scar size and reduced vascular afterload. Engraftment and trilineage differentiation was substantially greater with CSCs than with MSCs. Adult-cultured c-kit ؉ CSCs were less effective than fetal, but were still more potent than high-dose MSCs. These data demonstrate enhanced CSC engraftment, differentiation, and improved cardiac remodeling and function in ischemic heart failure. MSCs required a 30-fold greater dose than CSCs to improve cardiac function and anatomy. Together, these findings demonstrate a greater potency of CSCs than bone marrow MSCs in cardiac repair.

American journal of physiology. Heart and circulatory physiology, 2014

Duchenne muscular dystrophy may affect cardiac muscle, producing a dystrophic cardiomyopathy in h... more Duchenne muscular dystrophy may affect cardiac muscle, producing a dystrophic cardiomyopathy in humans and the mdx mouse. We tested the hypothesis that oxidative stress participates in disrupting calcium handling and contractility in the mdx mouse with established cardiomyopathy. We found increased expression (fivefold) of the NADPH oxidase (NOX) 2 in the mdx hearts compared with wild type, along with increased superoxide production. Next, we tested the impact of NOX2 inhibition on contractility and calcium handling in isolated cardiomyocytes. Contractility was decreased in mdx myocytes compared with wild type, and this was restored toward normal by pretreating with apocynin. In addition, the amplitude of evoked intracellular Ca(2+) concentration transients that was diminished in mdx myocytes was also restored with NOX2 inhibition. Total sarcoplasmic reticulum (SR) Ca(2+) content was reduced in mdx hearts and normalized by apocynin treatment. Additionally, NOX2 inhibition decreased ...

International Journal of Molecular Sciences

Maresin-1 (MaR1) is a specialized pro-resolving mediator, derived from omega-3 fatty acids, whose... more Maresin-1 (MaR1) is a specialized pro-resolving mediator, derived from omega-3 fatty acids, whose functions are to decrease the pro-inflammatory and oxidative mediators, and also to stimulate cell division. We investigated the hepatoprotective actions of MaR1 in a rat model of liver ischemia-reperfusion (IR) injury. MaR1 (4 ng/gr body weight) was administered prior to ischemia (1 h) and reperfusion (3 h), and controls received isovolumetric vehicle solution. To analyze liver function, transaminases levels and tissue architecture were assayed, and serum cytokines TNF-α, IL-6, and IL-10, mitotic activity index, and differential levels of NF-κB and Nrf-2 transcription factors, were analyzed. Transaminase, TNF-α levels, and cytoarchitecture were normalized with the administration of MaR1 and associated with changes in NF-κB. IL-6, mitotic activity index, and nuclear translocation of Nrf-2 increased in the MaR1-IR group, which would be associated with hepatoprotection and cell proliferat...

Free Radicals, Antioxidants and Diseases

The most important clinical consequence of coronary disease is acute myocardial infarction caused... more The most important clinical consequence of coronary disease is acute myocardial infarction caused by an occlusion that limits the irrigation to the heart. Although the gold standard treatment is to restore blood flow, this reperfusion causes inherent damage by increasing the size of the infarcted area primarily through the opening of the mitochondrial permeability transition pore (MPTP). The cardioprotective effect of nitric oxide (NO) has been described to operate through S-nitrosylation of several important proteins in the cardiomyocytes such as the calcium channels RyR2 and the L-type Ca 2+ channel and mitochondrial proteins, including the MPTP. In this sense, an attractive strategy to prevent the ischemia-reperfusion damage is to increase the bioavailability of endogenous Snitrosothiols. S-nitrosoglutathione reductase (GSNOR) is an enzyme involved in the metabolism of NO through denitrosylation, which would limit the cardioprotective effect of NO. Although inhibition of GSNOR has been studied in different organs, its effects on myocardial reperfusion have not yet been fully elucidated. In this chapter, we review the pathophysiology underlying myocardial reperfusion injury and the opening of the MPTP along with the cardioprotective role of S-nitrosothiols and the potential role for GSNOR.

International journal of molecular sciences, Jan 15, 2018

Cardiac aging is characterized by alterations in contractility and intracellular calcium ([Ca]) h... more Cardiac aging is characterized by alterations in contractility and intracellular calcium ([Ca]) homeostasis. It has been suggested that oxidative stress may be involved in this process. We and others have reported that in cardiomyopathies the NADPH oxidase (NOX)-derived superoxide is increased, with a negative impact on [Ca] and contractility. We tested the hypothesis that in the aged heart, [Ca] handling and contractility are disturbed by NOX-derived superoxide. For this we used adults (≈5 month-old) and aged (20⁻24 month-old) rats. Contractility was evaluated in isolated hearts, challenged with isoproterenol. To assess [Ca], isolated cardiac myocytes were field-stimulated and [Ca] was monitored with fura-2. Cardiac concentration-response to isoproterenol was depressed in aged compared to adults hearts ( < 0.005), but was restored by NOX inhibitors apocynin and VAS2870. In isolated cardiomyocytes, apocynin increased the amplitude of [Ca] in aged myocytes ( < 0.05). Time-50 [C...

Journal of Chemistry

Given the broad spectrum of biological uses of heteroaryl-acrylonitrile derivatives, it is necess... more Given the broad spectrum of biological uses of heteroaryl-acrylonitrile derivatives, it is necessary to find simple methods to synthesize and diversify this family of compounds. We report a stereoselective synthesis of a series of new (E)-2-(1H-indole-3-ylcarbonyl)-3-heteroaryl-acrylonitriles (3a–3i) obtained from 3-(cyanoacetyl)indole and heteroaryl-aldehydes under microwave-assisted Knoevenagel reaction at 300 W of potency and 100°C. The desired derivatives (3a–3i) were obtained with variable yields (30–94%) and time reactions (8–90 min). All the heteroaryl-acrylonitriles were characterized by physicoanalytical techniques such IR, 1H, 13C NMR, and electrospray mass spectrometry.

American journal of physiology. Heart and circulatory physiology, 2014

Journal of the Taiwan Institute of Chemical Engineers, 2015

Alzheimer disease (AD) is a neurodegenerative disorder that causes damages in brain due to factor... more Alzheimer disease (AD) is a neurodegenerative disorder that causes damages in brain due to factors such as oxidative stress, low-levels of the neurotransmitter acetylcholine, β-amyloid protein aggregation, etc. It is necessary the design of novel efficient drugs for AD treatment to counteract the increase of people suffering from AD. Recently, heteroaryl-acrylonitrile derivatives have emerged as a new family of acetylcholinesterase inhibitors (AChEIs). The analysis of the structure-activity relationship of these compounds could help to elucidate the main molecular features that contribute to the activity of these compounds. In this paper, we performed 3D-QSAR analyses through a Comparative Similarity Indices Analysis (CoMSIA) to determine the keyfactors for the activity of E/Z-heteroaryl-acrylonitriles reported in literature and novel derivatives that are reported in this work for the first time. The novel derivatives were synthetized in order to enlarge the library of compounds available in literature. They were synthetized via microwave-assisted Knoevenagel reaction and their biological activities as AChE/BuChE inhibitors were explored by the Ellman's spectrophotometric method. The best CoMSIA model included both electrostatic and hydrogen bond donor fields (CoMSIA-ED model) and provided the best statistical results with a highest Q 2 value of 0.901. The model also had satisfactory predictions of external compounds. Our in silico study provided a new tool for predicting the affinity of heteroaryl-acrylonitriles as AChEIs to the scientific community. It can be used for guiding the design and synthesis of novel, selective, and more potent AChEIs.

International journal of physiology, pathophysiology and pharmacology, 2014

NOS1AP gene (nitric oxide synthase 1-adaptor protein) is strongly associated with abnormalities i... more NOS1AP gene (nitric oxide synthase 1-adaptor protein) is strongly associated with abnormalities in the QT interval of the electrocardiogram and with sudden cardiac death. To determine the role of NOS1AP in the physiology of the cardiac myocyte, we assessed the impact of silencing NOS1AP, using siRNA, on [Ca(2+)]i transients in neonatal cardiomyocytes. In addition, we examined the co-localization of NOS1AP with cardiac ion channels, and finally, evaluated the expression of NOS1AP in a mouse model of dystrophic cardiomyopathy. Using siRNA, NOS1AP levels were reduced to ~30% of the control levels (p<0.05). NOS1AP silencing in cardiac myocytes reduced significantly the amplitude of electrically evoked calcium transients (p<0.05) and the degree of S-nitrosylation of the cells (p<0.05). Using confocal microscopy, we evaluated NOS1AP subcellular location and interactions with other proteins by co-localization analysis. NOS1AP showed a high degree of co-localization with the L-type...

Category: 1. Myocardial Ischemia/Infarction-Basic Session-Poster Board Number:

Journal of the American College of Cardiology, 2010

Journal of Cardiac Failure, 2010

Circulation, Nov 3, 2009

Circulation, Nov 25, 2014

Circulation, Nov 22, 2011

The Journal of Physiology, 2009

Circulation, 2011

American journal of physiology. Heart and circulatory physiology, 2014

International Journal of Molecular Sciences

Free Radicals, Antioxidants and Diseases

International journal of molecular sciences, Jan 15, 2018

Journal of Chemistry

American journal of physiology. Heart and circulatory physiology, 2014

Journal of the Taiwan Institute of Chemical Engineers, 2015

International journal of physiology, pathophysiology and pharmacology, 2014

Journal of Medicinal Food, 2014

Cardiovascular disease (CVD) is the leading cause of death worldwide. Healthy eating is among its... more Cardiovascular disease (CVD) is the leading cause of death worldwide. Healthy eating is among its safeguards, especially the daily intake of fruits and vegetables. In this context it has been shown that tomato (Solanum lycopersicum) presents antiplatelet activity. In the present study, we evaluated in vitro antiplatelet activity of fresh hybrid tomato process (nine hybrids: Apt 410, H 9888, Bos 8066, Sun 6366, AB3, HMX 7883, H 9665, H 7709, and H 9997), paste and its byproduct of industrial processes (pomace). We assessed antiplatelet activity ex vivo and bleeding time in rats that ingested 0.1 and 1.0 g/kg of pomace each day. In studies in vitro, no significant differences in antiplatelet activity was observed in fresh tomato hybrids. Furthermore, the agro-industrial process did not affect the antiplatelet activity of paste and pomace. Likewise, pomace intake of 1.0 g/kg per day prolonged bleeding time and reduced ex vivo platelet aggregation in rats. The data obtained indicate that tomato has one or more compounds that caused antiplatelet activity. Regular consumption of tomato and its industrial derivatives could be part of a CVD prevention regimen.

Stem Cells Translational Medicine, 2012

Proceedings of the National Academy of Sciences, 2007

Altered Ca 2؉ homeostasis is a salient feature of heart disease, where the calcium release channe... more Altered Ca 2؉ homeostasis is a salient feature of heart disease, where the calcium release channel ryanodine receptor (RyR) plays a major role. Accumulating data support the notion that neuronal nitric oxide synthase (NOS1) regulates the cardiac RyR via Snitrosylation. We tested the hypothesis that NOS1 deficiency impairs RyR S-nitrosylation, leading to altered Ca 2؉ homeostasis. Diastolic Ca 2؉ levels are elevated in NOS1 ؊/؊ and NOS1/NOS3 ؊/؊ but not NOS3 ؊/؊ myocytes compared with wild-type (WT), suggesting diastolic Ca 2؉ leakage. Measured leak was increased in NOS1 ؊/؊ and NOS1/NOS3 ؊/؊ but not in NOS3 ؊/؊ myocytes compared with WT. Importantly, NOS1 ؊/؊ and NOS1/NOS3 ؊/؊ myocytes also exhibited spontaneous calcium waves. Whereas the stoichiometry and binding of FK-binding protein 12.6 to RyR and the degree of RyR phosphorylation were not altered in NOS1 ؊/؊ hearts, RyR2 S-nitrosylation was substantially decreased, and the level of thiol oxidation increased. Together, these findings demonstrate that NOS1 deficiency causes RyR2 hyponitrosylation, leading to diastolic Ca 2؉ leak and a proarrhythmic phenotype. NOS1 dysregulation may be a proximate cause of key phenotypes associated with heart disease.

Proceedings of the National Academy of Sciences, 2010

Whether the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis exerts cardioprotective... more Whether the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis exerts cardioprotective effects remains controversial; and the underlying mechanism(s) for such actions are unclear.

Proceedings of the National Academy of Sciences, 2012

Although protein S-nitrosylation is increasingly recognized as mediating nitric oxide (NO) signal... more Although protein S-nitrosylation is increasingly recognized as mediating nitric oxide (NO) signaling, roles for protein denitrosylation in physiology remain unknown. Here, we show that S-nitrosoglutathione reductase (GSNOR), an enzyme that governs levels of S-nitrosylation by promoting protein denitrosylation, regulates both peripheral vascular tone and β-adrenergic agonist-stimulated cardiac contractility, previously ascribed exclusively to NO/cGMP. GSNOR-deficient mice exhibited reduced peripheral vascular tone and depressed β-adrenergic inotropic responses that were associated with impaired β-agonist-induced denitrosylation of cardiac ryanodine receptor 2 (RyR2), resulting in calcium leak. These results indicate that systemic hemodynamic responses (vascular tone and cardiac contractility), both under basal conditions and after adrenergic activation, are regulated through concerted actions of NO synthase/GSNOR and that aberrant denitrosylation impairs cardiovascular function. Our findings support the notion that dynamic S-nitrosylation/denitrosylation reactions are essential in cardiovascular regulation. excitation-contraction coupling | nitroso-redox imbalance

Proceedings of the National Academy of Sciences, 2012

Both cardiac myocytes and cardiac stem cells (CSCs) express the receptor of growth hormone releas... more Both cardiac myocytes and cardiac stem cells (CSCs) express the receptor of growth hormone releasing hormone (GHRH), activation of which improves injury responses after myocardial infarction (MI).

Journal of Biological Chemistry, 2010

S-Nitrosylation is a ubiquitous post-translational modification that regulates diverse biologic p... more S-Nitrosylation is a ubiquitous post-translational modification that regulates diverse biologic processes. In skeletal muscle, hypernitrosylation of the ryanodine receptor (RyR) causes sarcoplasmic reticulum (SR) calcium leak, but whether abnormalities of cardiac RyR nitrosylation contribute to dysfunction of cardiac excitation-contraction coupling remains controversial.

Clinical and Translational Science, 2011

Erythropoietin (EPO) has the potential to improve ischemic tissue by mobilizing endothelial proge... more Erythropoietin (EPO) has the potential to improve ischemic tissue by mobilizing endothelial progenitor cells and enhancing neovascularization. We hypothesized that combining EPO with human chorionic-gonadotrophin (hCG), would improve post-myocardial infarction (MI) effects synergistically.

Molecular Medicine Reports, 2014

The understanding of nitric oxide (NO) signaling has grown substantially since the identification... more The understanding of nitric oxide (NO) signaling has grown substantially since the identification of endothelial derived relaxing factor (EDRF). NO has emerged as a ubiquitous signaling molecule involved in diverse physiological and pathological processes. Perhaps the most significant function, independent of EDRF, is that of NO signaling mediated locally in signaling modules rather than relying upon diffusion. In this context, NO modulates protein function via direct post-translational modification of cysteine residues. This review explores NO signaling and related reactive nitrogen species involved in the regulation of the cardiovascular system. A critical concept in the understanding of NO signaling is that of the nitroso-redox balance. Reactive nitrogen species bioactivity is fundamentally linked to the production of reactive oxygen species. This interaction occurs at the chemical, enzymatic and signaling effector levels. Furthermore, the nitroso-redox equilibrium is in a delicate balance, involving the cross-talk between NO and oxygen-derived species signaling systems, including NADPH oxidases and xanthine oxidase.

Nitric oxide exerts ubiquitous signaling via post-translational modification of cysteine residues... more Nitric oxide exerts ubiquitous signaling via post-translational modification of cysteine residues, a reaction termed S-nitrosylation. Important substrates of S-nitrosylation that influence cardiac function include receptors, enzymes, ion channels, transcription factors, and structural proteins. Cardiac ion channels subserving excitation-contraction coupling are potentially regulated by S-nitrosylation. Specificity is achieved in part by spatial co-localization of ion channels with nitric oxide synthases (NOS), enzymatic sources of NO in biologic systems, and by coupling of NOS activity to localized calcium/second messenger concentrations. Ion channels regulate cardiac excitability and contractility in millisecond timescales raising the possibility that NO-related species modulate heart function on a beat-to beat basis. This review focuses on recent advances in understanding of NO regulation of the cardiac action potential, and of the calcium release channel ryanodine receptor, which is crucial for the generation of force. S-nitroso (SNO) signaling is disrupted in pathological states in which the redox state of the cell is dysregulated, including ischemia, heart failure, and atrial fibrillation.