Is Bauman's "liquid modernity" influencing the way we are doing science?

This commentary analyzes the possible effects of lightness—a typical attribute of modern (liquid) society, according to Bauman—on the way we are doing science. We share our opinion in an attempt to discern whether some unwanted practices that may affect our scientific results (such as technology misuse, bonus rewards, publishing under pressure, or indolence for getting accurate results) can be attributed, at least partially, to the liquid characteristic of modern society. We also examine whether the different systems that support science favor these actions, conspiring against what should be the primary goal of science: the search for truth. We finally consider several aspects that should be taken into account to rescue science from the intrusion of weightless actions.Fil: Mattiazzi, Ramona Alicia. 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: Vila Petroff, Martin Gerarde. 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

AKAP18δ Puts CaMKII in the Right Place at the Right Time: Implications for Cardiac Ca 2+ Handling

A delicate control of myocyte Ca2+ handling is essential for efficient excitation-contraction coupling (ECC) in the heart, and its alteration is associated with decreased contractility, arrhythmias, hypertrophy, and heart failure. During ECC, entry of Ca2+ from the extracellular space occurs through L-type Ca2+ channels and mediates Ca2+-dependent opening of RyR2 (ryanodine receptors) allowing massive movement of Ca2+ from the sarco-endoplasmic reticulum (SR) to the cytosol and ultimately triggering cell contraction. Thereafter, relaxation occurs primarily by the reuptake of Ca2+ into de SR by SERCA2a (SR Ca2+ ATPase 2a). Phosphorylation of proteins involved in Ca2+ cycling have critical functional consequences on ECC, including greater influx of Ca2+ through the L-type Ca2+ channels and a greater release of Ca2+ from the SR through RyR2 and a more efficient Ca2+ reuptake through SERCA2a as a result of phosphorylation of its regulatory protein PLN (phospholamban). Accumulating evidence indicates that spatial and temporal control of phosphorylation/dephosphorylation cycles are another crucial point of control of cardiac ECC. This control is achieved, at least in part, by a complex network of scaffolding, anchoring and adaptor proteins that recruit, compartmentalize, and regulate protein kinases in a location specific manner.1 AKAPs (A-kinase anchoring proteins) are the paradigm of this integrated regulatory system that have been extensively shown to coordinate spatially restricted cAMP-PKA (protein kinase A)-dependent signaling that provides a high level of specificity, contributing to adrenergic modulation of cardiomyocyte function.2 There are over 50 known AKAPs (including alternative-spliced forms) that target PKA to different sites within the cell. While AKAPs share their ability to bind PKA, they are remarkably diverse scaffolding proteins. Indeed, AKAPs couple PKA to different substrates, enhancing the rate and fidelity of their phosphorylation by the kinase. By bringing together different combinations of upstream and downstream signaling molecules, AKAPs provide the architectural infrastructure for specialization of the cAMP/PKA signaling network which is critical for the regulation of cardiac Ca2+ handling.Fil: Gonano, Luis Alberto. 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: Vila Petroff, Martin Gerarde. 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

Impact of RyR2 potentiation on myocardial function

This perspective attempts to shed light on an old and not yet solved controversy in cardiac physiology, i.e., the impact of increasing ryanodine receptor (RyR)2 open probability on myocardial function. Based on an already proven myocyte model, it was shown that increasing RyR2 open probability results in a purely short-lived increase in Ca2+ transient amplitude, and, therefore, it does not increase cardiac contractility. However, potentiation of RyR2 activity permanently enhances fractional Ca2+ release, shifting the intracellular Ca2+ transient versus sarcoplasmic reticulum (SR) Ca2+ content curve to a new state of higher efficiency. This would allow the heart to maintain a given contractility despite a decrease in SR Ca2+ content, to enhance contractility if SR Ca2+ content is simultaneously preserved or to successfully counteract the effects of a negative inotropic intervention. New & Noteworthy Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractility. However, RyR2 potentiation shifts the intracellular Ca2+ transient-sarcoplasmic reticulum (SR) Ca2+ content relationship toward an enhanced efficiency state, which may contribute to a positive inotropic effect, preserve contractility despite decreased SR Ca2+ content, or successfully counteract the effects of a negative inotropic actionCentro de Investigaciones Cardiovasculare

CaMKII-dependent responses to ischemia and reperfusion challenges in the heart

Ischemic heart disease is a leading cause of death, and there is considerable imperative to identify effective therapeutic interventions. Cardiomyocyte Ca2+ overload is a major cause of ischemia and reperfusion injury, initiating a cascade of events culminating in cardiomyocyte death, myocardial dysfunction, and occurrence of lethal arrhythmias. Responsive to fluctuations in intracellular Ca2+, Ca2+/calmodulin-dependent protein kinase II (CaMKII) has emerged as an enticing therapeutic target in the management of ischemic heart injury. CaMKII is activated early in ischemia and to a greater extent in the first few minutes of reperfusion, at a time when reperfusion arrhythmias are particularly prominent. CaMKII phosphorylates and upregulates many of the key proteins involved in intracellular Na+ and Ca2+ loading in ischemia and reperfusion. Experimentally, selective inhibition of CaMKII activity reduces cardiomyocyte death and arrhythmic incidence post-ischemia. New evidence is emerging that CaMKII actions in ischemia and reperfusion involve specific splice variant targeted actions, selective and localized post-translational modifications, and organelle-directed substrate interactions. A more complete mechanistic understanding of CaMKII mode of action in ischemia and reperfusion is required to optimize intervention opportunities. This review summarizes the current experimentally derived understanding of CaMKII participation in mediating the pathophysiology of the heart in ischemia and in reperfusion, and highlights priority future research directions.Centro de Investigaciones Cardiovasculare

Impact of RyR2 potentiation on myocardial function

This perspective attempts to shed light on an old and not yet solved controversy in cardiac physiology, i.e., the impact of increasing ryanodine receptor (RyR)2 open probability on myocardial function. Based on an already proven myocyte model, it was shown that increasing RyR2 open probability results in a purely short-lived increase in Ca2+ transient amplitude, and, therefore, it does not increase cardiac contractility. However, potentiation of RyR2 activity permanently enhances fractional Ca2+ release, shifting the intracellular Ca2+ transient versus sarcoplasmic reticulum (SR) Ca2+ content curve to a new state of higher efficiency. This would allow the heart to maintain a given contractility despite a decrease in SR Ca2+ content, to enhance contractility if SR Ca2+ content is simultaneously preserved or to successfully counteract the effects of a negative inotropic intervention. New & Noteworthy Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractility. However, RyR2 potentiation shifts the intracellular Ca2+ transient-sarcoplasmic reticulum (SR) Ca2+ content relationship toward an enhanced efficiency state, which may contribute to a positive inotropic effect, preserve contractility despite decreased SR Ca2+ content, or successfully counteract the effects of a negative inotropic actionCentro de Investigaciones Cardiovasculare

Exercise training corrects control of spontaneous calcium waves in hearts from myocardial infarction heart failure rats

Impaired cardiac control of intracellular diastolic Ca<sup>2+</sup> gives rise to arrhythmias. Whereas exercise training corrects abnormal cyclic Ca<sup>2+</sup> handling in heart failure, the effect on diastolic Ca<sup>2+</sup> remains unstudied. Here, we studied the effect of exercise training on the generation and propagation of spontaneous diastolic Ca<sup>2+</sup> waves in failing cardiomyocytes. Post-myocardial infarction heart failure was induced in Sprague–Dawley rats by coronary artery ligation. Echocardiography confirmed left ventricular infarctions of 40 ± 5%, whereas heart failure was indicated by increased left ventricular end-diastolic pressures, decreased contraction-relaxation rates, and pathological hypertrophy. Spontaneous Ca<sup>2+</sup> waves were imaged by laser linescanning confocal microscopy (488 nm excitation/505–530 nm emission) in 2 μM Fluo-3-loaded cardiomyocytes at 37°C and extracellular Ca<sup>2+</sup> of 1.2 and 5.0 mM. These studies showed that spontaneous Ca<sup>2+</sup> wave frequency was higher at 5.0 mM than 1.2 mM extracellular Ca<sup>2+</sup> in all rats, but failing cardiomyocytes generated 50% (P < 0.01) more waves compared to sham-operated controls at Ca<sup>2+</sup> 1.2 and 5.0 mM. Exercise training reduced the frequency of spontaneous waves at both 1.2 and 5.0 mM Ca2+ (P< 0.05), although complete normalization was not achieved. Exercise training also increased the aborted/completed ratio of waves at 1.2 mM Ca<sup>2+</sup> (P < 0.01), but not 5.0 mM. Finally, we repeated these studies after inhibiting the nitric oxide synthase with L-NAME. No differential effects were found; thus, mediation did not involve the nitric oxide synthase. In conclusion, exercise training improved the cardiomyocyte control of diastolic Ca<sup>2+</sup> by reducing the Ca<sup>2+</sup> wave frequency and by improving the ability to abort spontaneous Ca<sup>2+</sup> waves after their generation, but before cell-wide propagation

Na+-Ca2+ exchange function underlying contraction frequency inotropy in the rat myocardium

In most mammalian species, an increase in stimulation frequency (ISF) produces an increase in contractility (treppe phenomenon), which results from larger Ca2+ transients at higher frequencies, due to an increase in sarcoplasmic reticulum Ca2+ load and release. The present study attempts to elucidate the contribution of the Na+-Ca2+ exchanger (NCX) to this phenomenon. Isolated cat ventricular myocytes, loaded with [Ca2+]i- and [Na+]i-sensitive probes, were used to determine whether the contribution of the NCX to the positive inotropic effect of ISF is due to an increase in Ca2+ influx (reverse mode) and/or a decrease in Ca2+ efflux (forward mode) via the NCX, due to frequency-induced [Na+]i elevation, or whether it was due to the reduced time for the NCX to extrude Ca2+. The results showed that the positive intropic effect produced by ISF was temporally dissociated from the increase in [Na+]i and was not modified by KB-R7943 (1 or 5 μM), a specific blocker of the reverse mode of the NCX. Whereas the ISF from 10 to 30 beats min-1 (bpm) did not affect the forward mode of the NCX (assessed by the time to half-relaxation of the caffeine-induced Ca2+ transient), the ISF to 50 bpm produced a significant reduction of the activity of the forward mode of the NCX, which occurred in association with an increase in [Na+]i (from 4.33 ± 0.40 to 7.25 ± 0.50 mM). However, both changes became significant well after the maximal positive inotropic effect had been reached. In contrast, the positive inotropic effect produced by ISF from 10 to 50 bpm was associated with an increase in diastolic [Ca2+]i, which occurred in spite of a significant increase in the relaxation rate and at a time at which no increases in [Na+]i were detected. The contribution of the NCX to stimulus frequency inotropy would therefore depend on a decrease in NCX-mediated Ca2+ efflux due to the reduced diastolic interval between beats and not on [Na+]i-dependent mechanisms.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Rested-state contractions and rest potentiation in spontaneously hypertensive rats

To gain further insight into the excitation-contraction coupling mechanisms in hypertrophy, we studied rested-state contractions, rest decay curves, and rest potentiation under different experimental conditions using papillary muscles of spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar and Wistar-Kyoto (WKY) rats. Under constant stimulation at 1.1 Hz, contractility and relaxation were not significantly different in hypertensive when compared with normotensive animals. Rested-state contraction (the first beat after a rest interval of 15 minutes) increased to 159.2 ± 23% and 123.5 ± 7.5% of prerest values in Wistar and WKY rats, respectively, whereas in SHR it did not differ from prerest values (92.8 ± 9.8%). Ryanodine, used to preferentially inhibit sarcoplasmic reticulum function, eliminated the differences in rested-state contractions observed between hypertensive and normotensive rats. Maximal rest potentiation (the first beat after a rest interval of 1 minute) was also significantly higher in Wistar and WKY rats than in SHR. These differences persisted at low extracellular Na⁺, when Ca2+ efflux via the Na⁺-Ca2+ exchanger was inhibited. Rest decay curves (the decay in contractility from maximal rest potentiation to rested-state contraction) showed a similar pattern in the three rat strains. The results suggest that the altered inotropic responses of the SHR arise from an alteration in calcium handling by the sarcoplasmic reticulum. Experiments on saponin-skinned trabeculae indicated that fractional calcium release induced by caffeine was significantly reduced in the SHR. We conclude that the altered inotropic response observed in SHR may reflect a diminished release of calcium from the sarcoplasmic reticulum.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

TLR4 and NLRP3 Caspase 1- IL-1β- Axis are not Involved in Colon Ascendens Stent Peritonitis (Casp)-Associated Heart Disease

Hemodynamic collapse and myocardial dysfunction are among the major causes ofdeath in severe sepsis. The purpose of this study was to assess the role played by TLR4and by the NLRP3 inflammasome in the cardiac dysfunction that occurs after highgradepolymicrobial sepsis. We performed the colon ascendens stent peritonitis (CASP)surgery in Tlr4-/-, Nlrp3-/- and caspase-1-/- mice. We also assessed for the first time theelectrical heart function in the CASP model. The QJ interval was increased in wild-typeC57BL/6J mice after CASP when compared to sham controls, a result paralleled by anincrease in the cardiac action potential duration (APD). The decreases in ejectionfraction (EF), left-ventricle end diastolic volume (LVEDV), stroke volume, and cardiacoutput found after CASP were similar among all groups of mice. Similar heart responsewas found when Nlrp3-/- mice were submitted to high-grade CLP. Despite developingcardiac dysfunction similar to wild-types after CASP, Nlrp3-/- mice had reducedcirculating levels of IL-1β, IL-6 and TNF-α. Our results demonstrate that the geneticablation of Tlr4, Nlrp3, and caspase-1 does not prevent the cardiac dysfunction, despitepreventing the increase in pro-inflammatory cytokines, indicating that these are notfeasible targets to therapy in high-grade sepsis.Fil: López Alarcón, Maria Micaela. Universidade Federal do Rio de Janeiro; BrasilFil: Fernandez Ruocco, Maria Julieta. Universidade Federal do Rio de Janeiro; BrasilFil: Ferreira, Fabiano. Universidade Federal do Rio de Janeiro; BrasilFil: Paula Neto, Heitor A.. Universidade Federal do Rio de Janeiro; BrasilFil: Sepúlveda, Marisa Noemí. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; ArgentinaFil: Vila Petroff, Martin Gerarde. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares ; ArgentinaFil: Carvalho, Adriana Bastos. Universidade Federal do Rio de Janeiro; BrasilFil: Peroba Ramos, Isalira. Universidade Federal do Rio de Janeiro; BrasilFil: Branda, Hugo Justino. Universidade Federal do Rio de Janeiro; BrasilFil: Neto Paiva, Claudia. Universidade Federal do Rio de Janeiro; BrasilFil: Medei, Emiliano. Universidade Federal do Rio de Janeiro; Brasi

Angiotensin II-induced oxidative stress resets the Ca2+ dependence of Ca2+-calmodulin protein kinase II and promotes a death pathway conserved across different species

Rationale: Angiotensin (Ang) II-induced apoptosis was reported to be mediated by different signaling molecules. Whether these molecules are either interconnected in a single pathway or constitute different and alternative cascades by which Ang II exerts its apoptotic action, is not known. Objective: To investigate in cultured myocytes from adult cat and rat, 2 species in which Ang II has opposite inotropic effects, the signaling cascade involved in Ang II-induced apoptosis. Methods and results: Ang II (1 μmol/L) reduced cat/rat myocytes viability by ≈40%, in part, because of apoptosis (TUNEL/caspase-3 activity). In both species, apoptosis was associated with reactive oxygen species (ROS) production, Ca2+/calmodulin-dependent protein kinase (CaMK)II, and p38 mitogen-activated protein kinase (p38MAPK) activation and was prevented by the ROS scavenger MPG (2-mercaptopropionylglycine) or the NADPH oxidase inhibitor DPI (diphenyleneiodonium) by CaMKII inhibitors (KN-93 and AIP [autocamtide 2-related inhibitory peptide]) or in transgenic mice expressing a CaMKII inhibitory peptide and by the p38MAPK inhibitor, SB202190. Furthermore, p38MAPK overexpression exacerbated Ang II-induced cell mortality. Moreover, although KN-93 did not affect Ang II-induced ROS production, it prevented p38MAPK activation. Results further show that CaMKII can be activated by Ang II or H2O2, even in the presence of the Ca 2+chelator BAPTA-AM, in myocytes and in EGTA-Ca2-free solutions in the presence of the calmodulin inhibitor W-7 in in vitro experiments. Conclusions: (1) The Ang II-induced apoptotic cascade converges in both species, in a common pathway mediated by ROS-dependent CaMKII activation which results in p38MAPK activation and apoptosis. (2) In the presence of Ang II or ROS, CaMKII may be activated at subdiastolic Ca2+concentrations, suggesting a new mechanism by which ROS reset the Ca2+dependence of CaMKII to extremely low Ca2+levels.Facultad de Ciencias Médica