La Investigación como modus vivendi

Asociación Argentina para el Progreso de las Ciencias, merecida o no, me produce cierto halago y quiero agradecer a quienes me consideraron para hacerla. Sin embargo, para que la misma adquiera algún sentido, quisiera que esta pequeña crónica de mi camino en la investigación pueda significar algo menos mezquino que la satisfacción de mi ego y sirva para motivar y alentar a los jóvenes que se inician en este camino. Intentaré describir, lo más objetivamente posible el camino que inicié hace más de 50 años intentando develar los mecanismos básicos de la función cardíaca, camino que sigo transitando con entusiasmo. A los datos precisos he agregado algunas anécdotas contadas tal como han quedado en mi memoria después de tantos años.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"; Argentin

The role of CaMKII regulation of phospholamban activity in heart disease

Phospholamban (PLN) is a phosphoprotein in cardiac sarcoplasmic reticulum (SR) that is a reversible regulator of the Ca(2)(+)-ATPase (SERCA2a) activity and cardiac contractility. Dephosphorylated PLN inhibits SERCA2a and PLN phosphorylation, at either Ser(16) by PKA or Thr(17) by Ca(2)(+)-calmodulin-dependent protein kinase (CaMKII), reverses this inhibition. Through this mechanism, PLN is a key modulator of SR Ca(2)(+) uptake, Ca(2)(+) load, contractility, and relaxation. PLN phosphorylation is also the main determinant of β1-adrenergic responses in the heart. Although phosphorylation of Thr(17) by CaMKII contributes to this effect, its role is subordinate to the PKA-dependent increase in cytosolic Ca(2)(+), necessary to activate CaMKII. Furthermore, the effects of PLN and its phosphorylation on cardiac function are subject to additional regulation by its interacting partners, the anti-apoptotic HAX-1 protein and Gm or the anchoring unit of protein phosphatase 1. Regulation of PLN activity by this multimeric complex becomes even more important in pathological conditions, characterized by aberrant Ca(2)(+)-cycling. In this scenario, CaMKII-dependent PLN phosphorylation has been associated with protective effects in both acidosis and ischemia/reperfusion. However, the beneficial effects of increasing SR Ca(2)(+) uptake through PLN phosphorylation may be lost or even become deleterious, when these occur in association with alterations in SR Ca(2)(+) leak. Moreover, a major characteristic in human and experimental heart failure (HF) is depressed SR Ca(2)(+) uptake, associated with decreased SERCA2a levels and dephosphorylation of PLN, leading to decreased SR Ca(2)(+) load and impaired contractility. Thus, the strategy of altering SERCA2a and/or PLN levels or activity to restore perturbed SR Ca(2)(+) uptake is a potential therapeutic tool for HF treatment. We will review here the role of CaMKII-dependent phosphorylation of PLN at Thr(17) on cardiac function under physiological and pathological conditions

The role of CaMKII regulation of phospholamban activity in heart disease

Phospholamban (PLN) is a phosphoprotein in cardiac sarcoplasmic reticulum (SR) that is a reversible regulator of the Ca2+-ATPase (SERCA2a) activity and cardiac contractility. Dephosphorylated PLN inhibits SERCA2a and PLN phosphorylation, at either Ser16 by PKA or Thr17 by Ca2+-calmodulin-dependent protein kinase (CaMKII), reverses this inhibition. Through this mechanism, PLN is a key modulator of SR Ca2+ uptake, Ca2+ load, contractility, and relaxation. PLN phosphorylation is also the main determinant of ß1-adrenergic responses in the heart. Although phosphorylation of Thr17 by CaMKII contributes to this effect, its role is subordinate to the PKA-dependent increase in cytosolic Ca2+, necessary to activate CaMKII. Furthermore, the effects of PLN and its phosphorylation on cardiac function are subject to additional regulation by its interacting partners, the anti-apoptotic HAX-1 protein and Gm or the anchoring unit of protein phosphatase 1. Regulation of PLN activity by this multimeric complex becomes even more important in pathological conditions, characterized by aberrant Ca2+-cycling. In this scenario, CaMKII-dependent PLN phosphorylation has been associated with protective effects in both acidosis and ischemia/reperfusion. However, the beneficial effects of increasing SR Ca2+ uptake through PLN phosphorylation may be lost or even become deleterious, when these occur in association with alterations in SR Ca2+ leak. Moreover, a major characteristic in human and experimental heart failure (HF) is depressed SR Ca2+ uptake, associated with decreased SERCA2a levels and dephosphorylation of PLN, leading to decreased SR Ca2+ load and impaired contractility. Thus, the strategy of altering SERCA2a and/or PLN levels or activity to restore perturbed SR Ca2+ uptake is a potential therapeutic tool for HF treatment. We will review here the role of CaMKII-dependent phosphorylation of PLN at Thr17 on cardiac function under physiological and pathological conditions.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Targeting late ICaL to close the window to ventricular arrhythmias

Triggered arrhythmias originate from aberrant cell membrane depolarizations that occur during or after completion of the cardiac action potential (AP). Although the phenomenon was recognized early and associated with cardiac arrhythmias in recordings relying on monophasic APs (Segers, 1941; Bozler, 1943), the concept of triggered activity was coined several decades later by Paul Cranefield (Cranefield, 1975) who, incidentally, served as editor-in-chief of this journal for more than 25 yr. This new term aimed to differentiate the slow membrane depolarization that depends on a previous AP (triggered activity) from automaticity, a slow membrane depolarization with different properties like the rhythmicity and spontaneity and independence on a preceding AP. Cranefield also originated the term “afterdepolarizations” for this triggered activity and described what are now traditionally known as early afterdepolarizations (EADs) “…that appears before the membrane potential has returned to the level it had at the beginning of the upstroke of the action potential,” and delayed afterdepolarizations (DADs), which occur “…after repolarization is complete i.e., after the membrane potential has returned to the level seen before the action potential” (Cranefield, 1975, 1977).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: 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"; Argentin

Tracking nitroxyl-derived posttranslational modifications of phospholamban in cardiac myocytes

Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Calcium (Ca2+) mishandling is one of the most striking abnormalities in this wide spectrum of pathologies, among which heart failure (HF) remains the leading cause of death in developed countries (Benjamin et al., 2018). A hallmark of HF in both human and animal models is impaired Ca2+ sequestration into the SR, which contributes to the decreased contractile performance in this disease (Gwathmey et al., 1987; Meyer et al., 1995; del Monte et al., 2002). Not surprisingly, this defective mechanism has been targeted with novel therapeutic strategies that are now undergoing experimental and clinical testing in animals and patients (Pfeffer et al., 2015; Hulot et al., 2016, 2017; Motloch et al., 2018). In this issue of JGP, Keceli et al. provide novel insights into the molecular mechanism from which nitroxyl (HNO), nitric oxide (NO)´s one-electron-reduced and protonated sibling, recently emerged as a promising candidate for HF treatment.Fil: Mundiña, Cecilia Beatriz. 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: 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"; Argentin

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

Ca2+/calmodulin-dependent protein kinase: A key component in the contractile recovery from acidosis

Intracellular acidosis exerts substantial effects on the contractile performance of the heart. Soon after the onset of acidosis, contractility diminishes, largely due to a decrease in myofilament Ca2+ responsiveness. This decrease in contractility is followed by a progressive recovery that occurs despite the persistent acidosis. This recovery is the result of different mechanisms that converge to increase diastolic Ca2+ levels and Ca2+ transient amplitude. Recent experimental evidence indicates that activation of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) is an essential step in the sequence of events that increases the Ca2+ transient amplitude and produces contractile recovery. CaMKII may act as an amplifier, providing compensatory pathways to offset the inhibitory effects of acidosis on many of the Ca2+ handling proteins. CaMKII-induced phosphorylation of the SERCA2a regulatory protein phospholamban (PLN) has the potential to promote an increase in sarcoplasmic reticulum (SR) Ca2+ uptake and SR Ca2+ load, and is a likely candidate to mediate the mechanical recovery from acidosis. In addition, CaMKII-dependent phosphorylation of proteins other than PLN may also contribute to this recovery.Facultad de Ciencias Médica

Ca2+/calmodulin-dependent protein kinase: A key component in the contractile recovery from acidosis

Intracellular acidosis exerts substantial effects on the contractile performance of the heart. Soon after the onset of acidosis, contractility diminishes, largely due to a decrease in myofilament Ca2+ responsiveness. This decrease in contractility is followed by a progressive recovery that occurs despite the persistent acidosis. This recovery is the result of different mechanisms that converge to increase diastolic Ca2+ levels and Ca2+ transient amplitude. Recent experimental evidence indicates that activation of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) is an essential step in the sequence of events that increases the Ca2+ transient amplitude and produces contractile recovery. CaMKII may act as an amplifier, providing compensatory pathways to offset the inhibitory effects of acidosis on many of the Ca2+ handling proteins. CaMKII-induced phosphorylation of the SERCA2a regulatory protein phospholamban (PLN) has the potential to promote an increase in sarcoplasmic reticulum (SR) Ca2+ uptake and SR Ca2+ load, and is a likely candidate to mediate the mechanical recovery from acidosis. In addition, CaMKII-dependent phosphorylation of proteins other than PLN may also contribute to this recovery.Facultad de Ciencias Médica

Phospholamban: a tiny protein with a prominent role in the regulation of cardiac relaxation and contractility

Phospholamban (PLN) is a small sarcoplasmic reticulum (SR) protein that in the dephosphorylated state tonically inhibits the SR Ca2+-ATPase (SERCA2a). Different type of evidence to be described, points to PLN as a crucial regulator of basal cardiac Ca2+ cycling, contractility and relaxation and as a main determinant of β -adrenergic stimulatory responses in vivo. The involvement of PLN and PLN phosphorylation under pathological conditions will be also discussed.Centro de Investigaciones Cardiovasculare

Unbalance between sarcoplasmic reticulum Ca2 + uptake and release: A first step toward Ca2 + triggered arrhythmias and cardiac damage

The present review focusses on the regulation and interplay of cardiac SR Ca2+ handling proteins involved in SR Ca2+ uptake and release, i.e., SERCa2/PLN and RyR2. Both RyR2 and SERCA2a/PLN are highly regulated by post-translational modifications and/or different partners’ proteins. These control mechanisms guarantee a precise equilibrium between SR Ca2+ reuptake and release. The review then discusses how disruption of this balance alters SR Ca2+ handling and may constitute a first step toward cardiac damage and malignant arrhythmias. In the last part of the review, this concept is exemplified in different cardiac diseases, like prediabetic and diabetic cardiomyopathy, digitalis intoxication and ischemia-reperfusion injury.Fil: Federico, Marilén. 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: Valverde, Carlos Alfredo. 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: 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: Palomeque, Julieta. 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"; Argentina. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; Argentin