Mitochondrial NHE1: a newly identified target to prevent heart disease

Mitochondrial damage has been associated with early steps of cardiac dysfunction in heart subjected to ischemic stress, oxidative stress and hypertrophy. A common feature for the mitochondrial deterioration is the loss of the mitochondrial membrane potential (δψm) with the concomitant irreversible opening of the mitochondrial permeability transition pore (MPTP) which follows the mitochondrial Ca2+ overload, and the subsequent mitochondrial swelling. We have recently characterized the expression of the Na+/H+ exchanger 1 (mNHE1) in mitochondrial membranes. This surprising observation provided a unique target for the prevention of the Ca2+-induced MPTP opening, based on the inhibition of the NHE1 m. In this line, inhibition of NHE1 m activity and/or reduction of NHE1 m expression decreased the Ca2+-induced mitochondrial swelling and the release of reactive oxygen species (ROS) in isolated cardiac mitochondria and preserved the δψm in isolated cardiomyocytes. Mitochondrial NHE1 thus represents a novel target to prevent cardiac disease, opening new avenues for future research.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Mitochondrial NHE1: a newly identified target to prevent heart disease

Mitochondrial damage has been associated with early steps of cardiac dysfunction in heart subjected to ischemic stress, oxidative stress and hypertrophy. A common feature for the mitochondrial deterioration is the loss of the mitochondrial membrane potential (δψm) with the concomitant irreversible opening of the mitochondrial permeability transition pore (MPTP) which follows the mitochondrial Ca2+ overload, and the subsequent mitochondrial swelling. We have recently characterized the expression of the Na+/H+ exchanger 1 (mNHE1) in mitochondrial membranes. This surprising observation provided a unique target for the prevention of the Ca2+-induced MPTP opening, based on the inhibition of the NHE1 m. In this line, inhibition of NHE1 m activity and/or reduction of NHE1 m expression decreased the Ca2+-induced mitochondrial swelling and the release of reactive oxygen species (ROS) in isolated cardiac mitochondria and preserved the δψm in isolated cardiomyocytes. Mitochondrial NHE1 thus represents a novel target to prevent cardiac disease, opening new avenues for future research.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Autocrine stimulation of cardiac Na+-Ca2+ exchanger currents by endogenous endothelin released by angiotensin II

The goal of the present study was to evaluate the effects of Ang II on the current produced by the Na+-Ca2+ exchanger (INCX) working in the reverse mode and the possible autocrine role played by the release of endothelin (ET) in these actions. INCX was studied in isolation in cat cardiac myocytes. Angiotensin II (Ang II) (100 nmol/L) increased INCX at potentials higher than 0 mV (at +60 mV: 2.07±0.22 pA/pF in control versus 2.73±0.22 pA/pF in Ang II, n = 9; P NCX induced by Ang II was prevented by the treatment of the cells with the unspecific blocker of the ET receptors, TAK 044 (1 μmol/L) (at +60 mV: 2.15±0.27 pA/pF in control versus 2.01±0.26 pA/pF in Ang II, n=5, NS). These results show, for the first time, that the effect of Ang II on INCX is the result of the autocrine actions of ET released by the octapeptide.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Mitochondrial NHE1: a newly identified target to prevent heart disease

Mitochondrial damage has been associated with early steps of cardiac dysfunction in heart subjected to ischemic stress, oxidative stress and hypertrophy. A common feature for the mitochondrial deterioration is the loss of the mitochondrial membrane potential (δψm) with the concomitant irreversible opening of the mitochondrial permeability transition pore (MPTP) which follows the mitochondrial Ca2+ overload, and the subsequent mitochondrial swelling. We have recently characterized the expression of the Na+/H+ exchanger 1 (mNHE1) in mitochondrial membranes. This surprising observation provided a unique target for the prevention of the Ca2+-induced MPTP opening, based on the inhibition of the NHE1 m. In this line, inhibition of NHE1 m activity and/or reduction of NHE1 m expression decreased the Ca2+-induced mitochondrial swelling and the release of reactive oxygen species (ROS) in isolated cardiac mitochondria and preserved the δψm in isolated cardiomyocytes. Mitochondrial NHE1 thus represents a novel target to prevent cardiac disease, opening new avenues for future research.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Autocrine stimulation of cardiac Na+-Ca2+ exchanger currents by endogenous endothelin released by angiotensin II

The goal of the present study was to evaluate the effects of Ang II on the current produced by the Na+-Ca2+ exchanger (INCX) working in the reverse mode and the possible autocrine role played by the release of endothelin (ET) in these actions. INCX was studied in isolation in cat cardiac myocytes. Angiotensin II (Ang II) (100 nmol/L) increased INCX at potentials higher than 0 mV (at +60 mV: 2.07±0.22 pA/pF in control versus 2.73±0.22 pA/pF in Ang II, n = 9; P NCX induced by Ang II was prevented by the treatment of the cells with the unspecific blocker of the ET receptors, TAK 044 (1 μmol/L) (at +60 mV: 2.15±0.27 pA/pF in control versus 2.01±0.26 pA/pF in Ang II, n=5, NS). These results show, for the first time, that the effect of Ang II on INCX is the result of the autocrine actions of ET released by the octapeptide.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Oxidative stress and cardiac contractility: a double edge sword?

The stretch of cardiac muscle increases developed force in two phases. The first phase occurs immediately after stretch and is the expression of the Frank–Starling mechanism, while the second one or slow force response (SFR) occurs gradually and is due to an increase in the calcium transient amplitude. Previously, we have shown that the SFR is the mechanical manifestation of an autocrine/paracrine mechanism activated by wall stretch involving growth factors-triggered reactive oxygen species (ROS) formation, and followed by redox-mediated cardiac Na+ /H+ exchanger (NHE1) activation leading to an increase in the Ca2+ "transient" amplitude. Recent own experiments assigned a role to thioredoxin-1 (“TRX1”, an important cellular antioxidant enzymatic system) in the development of the SFR. Interestingly, cardiac hypertrophy and failure, two of the most important health problems in western societies, are both triggered by intracellular signals triggered by myocardial stretch, being oxidative stress a critical step for its progression. Remarkably, experimental evidence has revealed that TRX1 overexpression negatively regulates cardiac hypertrophy. In this scenario, this short review was meant to briefly discuss the physiological, but potentially pathological, role of oxidative stress following myocardial stretch.El estiramiento miocárdico produce una respuesta contráctil en dos fases: un aumento rápido inmediato que es la expresión del mecanismo de Frank-Starling, y uno lento posterior denominado segunda fase de fuerza (SFF). En trabajos anteriores hemos mostrado que la SFF es la manifestación mecánica de un mecanismo autocrino/paracrino disparado por el estiramiento, que involucra liberación de factores de crecimiento seguida de la activación redox-dependiente del intercambiador Na+ /H+ cardíaco (NHE1) que conduce a un aumento Na+ -dependiente del Ca2+ intracelular. Experimentos más recientes de nuestro grupo han demostrado además que la tioredoxina-1 (“TRX1”, importante sistema enzimático antioxidante a nivel celular) es capaz de modular la magnitud de la SFF. Interesantemente, la hipertrofia y la insuficiencia cardíaca, dos de los problemas de salud más importantes en sociedades occidentales, se desencadenan por señales intracelulares que ocurren después del estiramiento miocárdico e incluyen estrés oxidativo como factor clave para su progresión patológica. En conexión, se ha demostrado que la sobreexpresión de TRX1 regula negativamente la hipertrofia cardíaca. En este escenario, esta revisión tiene como objetivo discutir brevemente el papel fisiológico, pero potencialmente patológico, del estrés oxidativo disparado por el estiramiento del miocardio.Fil: Zavala, Maite Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Diaz, Romina Gisel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Perez, Nestor Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Villa-Abrille, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentin

Thioredoxin 1 (TRX1) Overexpression Cancels the Slow Force Response (SFR) Development

The stretch of cardiac muscle increases developed force in two phases. The first phase occurs immediately after stretch and is the expression of the Frank–Starling mechanism, while the second one or slow force response (SFR) occurs gradually and is due to an increase in the calcium transient amplitude. An important step in the chain of events leading to the SFR generation is the increased production of reactive oxygen species (ROS) leading to redox sensitive ERK1/2, p90RSK, and NHE1 phosphorylation/activation. Conversely, suppression of ROS production blunts the SFR. The purpose of this study was to explore whether overexpression of the ubiquitously expressed antioxidant molecule thioredoxin-1 (TRX1) affects the SFR development and NHE1 phosphorylation. We did not detect any change in basal phopho-ERK1/2, phopho-p90RSK, and NHE1 expression in mice with TRX1 overexpression compared to wild type (WT). Isolated papillary muscles from WT or TRX1-overexpressing mice were stretched from 92 to 98% of its maximal length. A prominent SFR was observed in WT mice that was completely canceled in TRX1 animals. Interestingly, myocardial stretch induced a significant increase in NHE1 phosphorylation in WT mice that was not detected in TRX1-overexpressing mice. These novel results suggest that magnification of cardiac antioxidant defense power by overexpression of TRX1 precludes NHE1 phosphorylation/activation after stretch, consequently blunting the SFR development.Fil: Zavala, Maite Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Diaz, Romina Gisel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Villa-Abrille, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Perez, Nestor Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentin

Autocrine stimulation of cardiac Na+-Ca2+ exchanger currents by endogenous endothelin released by angiotensin II

The goal of the present study was to evaluate the effects of Ang II on the current produced by the Na+-Ca2+ exchanger (INCX) working in the reverse mode and the possible autocrine role played by the release of endothelin (ET) in these actions. INCX was studied in isolation in cat cardiac myocytes. Angiotensin II (Ang II) (100 nmol/L) increased INCX at potentials higher than 0 mV (at +60 mV: 2.07±0.22 pA/pF in control versus 2.73±0.22 pA/pF in Ang II, n = 9; P NCX induced by Ang II was prevented by the treatment of the cells with the unspecific blocker of the ET receptors, TAK 044 (1 μmol/L) (at +60 mV: 2.15±0.27 pA/pF in control versus 2.01±0.26 pA/pF in Ang II, n=5, NS). These results show, for the first time, that the effect of Ang II on INCX is the result of the autocrine actions of ET released by the octapeptide.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

A Cross-Country Empirical Analysis of Determinants of Clean Development Mechanism (CDM) Projects

The CDM seems to play a significant role in international GHG reduction activities. Yet, a few emerging countries have hosted majority of CDM projects whereas most LDCs have not hosted CDM projects at all. Given the current distributional imbalance, this study aims to identify determinants of CDM project hosting based on an empirical analysis using the tobit model. On the basis of the literature review, this study focuses on two factors, namely the host countries’ qualities of business environment and scientific level. As a result, this study finds the significance of business environment for both bilateral and unilateral CDM projects. Likewise, the significance of scientific and technical level is confirmed especially for unilateral CDM projects. Finally, this article suggests that eligible host countries should focus exclusively on the improvement of controllable determinants such as business environment to attract CDM investors. In addition, it is likely to be better for eligible host countries with low GHG emissions to develop CDM projects unilaterally using programmatic CDM due to their lower economic attractiveness

Cardioprotective role of IGF-1 in the hypertrophied myocardium of the spontaneously hypertensive rats: A key effect on NHE-1 activity

Aim: Myocardial Na+/H+ exchanger-1 (NHE-1) hyperactivity and oxidative stress are interrelated phenomena playing pivotal roles in the development of pathological cardiac hypertrophy and heart failure. Exercise training is effective to convert pathological into physiological hypertrophy in the spontaneously hypertensive rats (SHR), and IGF-1—key humoral mediator of exercise training—inhibits myocardial NHE-1, at least in normotensive rats. Therefore, we hypothesize that IGF-1 by hampering NHE-1 hyperactivity and oxidative stress should exert a cardioprotective effect in the SHR. Methods: NHE-1 activity [proton efflux (JH+) mmol L-1 min-1], expression and phosphorylation; H2O2 production; superoxide dismutase (SOD) activity; contractility and calcium transients were measured in SHR hearts in the presence/absence of IGF-1. Results: IGF-1 significantly decreased NHE-1 activity (JH+ at pHi 6.95: 1.39 ± 0.32, n = 9 vs C 3.27 ± 0.3, n = 20, P 2O2 production accompanied by an increase in SOD activity. In addition, IGF-1 improved cardiomyocyte contractility as evidenced by an increase in sarcomere shortening and a decrease in the relaxation constant, underlined by an increase in the amplitude and rate of decay of the calcium transients. Conclusion: IGF-1 exerts a cardioprotective role on the hypertrophied hearts of the SHR, in which the inhibition of NHE-1 hyperactivity, as well as the positive inotropic and antioxidant effects, emerges as key players.Centro de Investigaciones Cardiovasculare