Oxidative Post-translational Protein Modifications upon Ischemia/Reperfusion Injury.

While reperfusion, or restoration of coronary blood flow in acute myocardial infarction, is a requisite for myocardial salvage, it can paradoxically induce a specific damage known as ischemia/reperfusion (I/R) injury. Our understanding of the precise pathophysiological molecular alterations leading to I/R remains limited. In this study, we conducted a comprehensive and unbiased time-course analysis of post-translational modifications (PTMs) in the post-reperfused myocardium of two different animal models (pig and mouse) and evaluated the effect of two different cardioprotective therapies (ischemic preconditioning and neutrophil depletion). In pigs, a first wave of irreversible oxidative damage was observed at the earliest reperfusion time (20 min), impacting proteins essential for cardiac contraction. A second wave, characterized by irreversible oxidation on different residues and reversible Cys oxidation, occurred at late stages (6-12 h), affecting mitochondrial, sarcomere, and inflammation-related proteins. Ischemic preconditioning mitigated the I/R damage caused by the late oxidative wave. In the mouse model, the two-phase pattern of oxidative damage was replicated, and neutrophil depletion mitigated the late wave of I/R-related damage by preventing both Cys reversible oxidation and irreversible oxidation. Altogether, these data identify protein PTMs occurring late after reperfusion as an actionable therapeutic target to reduce the impact of I/R injury.

MCJ: A mitochondrial target for cardiac intervention in pulmonary hypertension.

Pulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies. Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure. These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition.

Role of UCP2 in the Energy Metabolism of the Cancer Cell Line A549.

The uncoupling protein UCP2 is a mitochondrial carrier for which transport activity remains controversial. The physiological contexts in which UCP2 is expressed have led to the assumption that, like UCP1, it uncouples oxidative phosphorylation and thereby reduces the generation of reactive oxygen species. Other reports have involved UCP2 in the Warburg effect, and results showing that UCP2 catalyzes the export of matrix C4 metabolites to facilitate glutamine utilization suggest that the carrier could be involved in the metabolic adaptations required for cell proliferation. We have examined the role of UCP2 in the energy metabolism of the lung adenocarcinoma cell line A549 and show that UCP2 silencing decreased the basal rate of respiration, although this inhibition was not compensated by an increase in glycolysis. Silencing did not lead to either changes in proton leakage, as determined by the rate of respiration in the absence of ATP synthesis, or changes in the rate of formation of reactive oxygen species. The decrease in energy metabolism did not alter the cellular energy charge. The decreased cell proliferation observed in UCP2-silenced cells would explain the reduced cellular ATP demand. We conclude that UCP2 does not operate as an uncoupling protein, whereas our results are consistent with its activity as a C4-metabolite carrier involved in the metabolic adaptations of proliferating cells.

Novel Molecular Mechanisms Involved in the Medical Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe condition with a high mortality rate despite advances in diagnostic and therapeutic strategies. In recent years, significant scientific progress has been made in the understanding of the underlying pathobiological mechanisms. Since current available treatments mainly target pulmonary vasodilation, but lack an effect on the pathological changes that develop in the pulmonary vasculature, there is need to develop novel therapeutic compounds aimed at antagonizing the pulmonary vascular remodeling. This review presents the main molecular mechanisms involved in the pathobiology of PAH, discusses the new molecular compounds currently being developed for the medical treatment of PAH and assesses their potential future role in the therapeutic algorithms of PAH.

Thrombosis Models: An Overview of Common In Vivo and In Vitro Models of Thrombosis.

Occlusions in the blood vessels caused by blood clots, referred to as thrombosis, and the subsequent outcomes are leading causes of morbidity and mortality worldwide. In vitro and in vivo models of thrombosis have advanced our understanding of the complex pathways involved in its development and allowed the evaluation of different therapeutic approaches for its management. This review summarizes different commonly used approaches to induce thrombosis in vivo and in vitro, without detailing the protocols for each technique or the mechanism of thrombus development. For ease of flow, a schematic illustration of the models mentioned in the review is shown below. Considering the number of available approaches, we emphasize the importance of standardizing thrombosis models in research per study aim and application, as different pathophysiological mechanisms are involved in each model, and they exert varying responses to the same carried tests. For the time being, the selection of the appropriate model depends on several factors, including the available settings and research facilities, the aim of the research and its application, and the researchers' experience and ability to perform surgical interventions if needed.

Neutrophil ß1 adrenoceptor blockade blunts stroke-associated neuroinflammation.

BACKGROUND AND PURPOSE: Reperfusion therapy is the standard of care for ischaemic stroke; however, there is a need to identify new therapeutic targets able to ameliorate cerebral damage. Neutrophil ß1 adrenoceptors (ß1AR) have been linked to neutrophil migration during exacerbated inflammation. Given the central role of neutrophils in cerebral damage during stroke, we hypothesize that ß1AR blockade will improve stroke outcomes. EXPERIMENTAL APPROACH: Rats were subjected to middle cerebral artery occlusion-reperfusion to evaluate the effect on stroke of the selective ß1AR blocker metoprolol (12.5 mg·kg-1 ) when injected i.v. 10 min before reperfusion. KEY RESULTS: Magnetic resonance imaging and histopathology analysis showed that pre-reperfusion i.v. metoprolol reduced infarct size. This effect was accompanied by reduced cytotoxic oedema at 24 h and vasogenic oedema at 7 days. Metoprolol-treated rats showed reduced brain neutrophil infiltration and those which infiltrated displayed a high proportion of anti-inflammatory phenotype (N2, YM1+ ). Additional inflammatory models demonstrated that metoprolol specifically blocked neutrophil migration via ß1AR and excluded a significant effect on the glia compartment. Consistently, metoprolol did not protect the brain in neutrophil-depleted rats upon stroke. In patients suffering an ischaemic stroke, ß1AR blockade by metoprolol reduced circulating neutrophil-platelet co-aggregates. CONCLUSIONS AND IMPLICATIONS: Our findings describe that ß1AR blockade ameliorates cerebral damage by targeting neutrophils, identifying a novel therapeutic target to improve outcomes in patients with stroke. This therapeutic strategy is in the earliest stages of the translational pathway and should be further explored.

Beta-3 adrenergic receptor overexpression reverses aortic stenosis-induced heart failure and restores balanced mitochondrial dynamics.

Aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and heart failure (HF). There is a lack of therapies able to prevent/revert AS-induced HF. Beta3 adrenergic receptor (ß3AR) signaling is beneficial in several forms of HF. Here, we studied the potential beneficial effect of ß3AR overexpression on AS-induced HF. Selective ß3AR stimulation had a positive inotropic effect. Transgenic mice constitutively overexpressing human ß3AR in the heart (c-hß3tg) were protected from the development of HF in response to induced AS, and against cardiomyocyte mitochondrial dysfunction (fragmented mitochondria with remodeled cristae and metabolic reprogramming featuring altered substrate use). Similar beneficial effects were observed in wild-type mice inoculated with adeno-associated virus (AAV9) inducing cardiac-specific overexpression of human ß3AR before AS induction. Moreover, AAV9-hß3AR injection into wild-type mice at late disease stages, when cardiac hypertrophy and metabolic reprogramming are already advanced, reversed the HF phenotype and restored balanced mitochondrial dynamics, demonstrating the potential of gene-therapy-mediated ß3AR overexpression in AS. Mice with cardiac specific ablation of Yme1l (cYKO), characterized by fragmented mitochondria, showed an increased mortality upon AS challenge. AAV9-hß3AR injection in these mice before AS induction reverted the fragmented mitochondria phenotype and rescued them from death. In conclusion, our results step out that ß3AR overexpression might have translational potential as a therapeutic strategy in AS-induced HF.

RAICEX: A Successful Story of the Spanish Scientific Diaspora.

RAICEX (Red de Asociaciones de Investigadores y Científicos Españoles en el Exterior), the Network of Associations of Spanish Researchers and Scientist Abroad, consists of more than 4,000 Spanish researchers distributed in 18 countries in 5 different continents. RAICEX was established in July 2018 by 15 foundational members: the associations of Spanish Researchers in the USA, México, Ireland, Sweden, Denmark, France, Italy, Japan, Australia, China, UK, Germany, Switzerland, Belgium, and Norway. Since then, 3 more associations have joined: Emirates, Netherlands and South Africa. RAICEX was born with the main goal: "promoting the exchange of experiences and knowledge between Spanish researchers and scientists abroad and all the stakeholders of the Spanish System of Science, Technology and Innovation (SECTI), serving as an advisory body, information channel and catalyst for international relations in scientific matters, contributing to the progress of science." Their main objectives are: (1) to provide support to researchers and scientists in mobility and personal development, offering training, information and guidance, as well as providing contact with all the other associations that make up the global network; (2) to disseminate and give visibility to the value of Science and the work of researchers and scientists, promoting communication of the advances of knowledge in all areas of society; (3) to promote international relations and cooperation between researchers / scientists and public and private organizations, from a global perspective; (4) to share the acquired knowledge and experience in different research and science systems abroad to advise, provide feedback and contribute to the progress of the whole SECTI. In this Case Study a particular scenario of the Spanish scientific diaspora, including history, reasons for going abroad, and consequences for the Spanish R&D system, shall be introduced to readers. The impact that RAICEX and its foundational members have had in the Spanish National System since the creation of the first community in the UK by 2012 will also be discussed. RAICEX's activities range from providing advice to newcomers and carrying out science dissemination, to becoming an advisory body to governments and institutions. The Spanish scientific diaspora is an extensive network committed to cooperation and brain connection.

Goat Milk Exosomes As Natural Nanoparticles for Detecting Inflammatory Processes By Optical Imaging.

Exosomes are cell-derived nanovesicles with a proven intercellular signaling role in inflammation processes and immune response. Due to their natural origin and liposome-like structure, these nanometer-scale vesicles have emerged as novel platforms for therapy and diagnosis. In this work, goat milk exosomes are isolated and fully characterized in terms of their physicochemical properties, proteomics, and biochemical profile in healthy mice, and used to detect inflammatory processes by optical imaging. For the in vitro and in vivo experiments, the exosomes are covalently labeled with the commercial fluorophores sulfo-Cyanine 5 and BODIPY-FL to create nanoprobes. In vitro studies using confocal imaging, flow cytometry, and colorimetric assays confirm the internalization of the nanoprobes as well their lack of cytotoxicity in macrophage populations RAW 264.7. Optical imaging in the mouse peritoneal region confirms the in vivo ability of one of the nanoprobes to localize inflammatory processes. In vivo imaging shows exosome uptake in the inflamed peritoneal region, and flow-cytometric analysis of peritonitis exudates confirms the uptake by macrophage and neutrophil populations. These results support the promising use of goat milk exosomes as natural probes in the detection of inflammatory processes.

Coronary microcirculation damage in anthracycline cardiotoxicity.

AIMS: The aim of this study was to study changes in coronary microcirculation status during and after several cycles of anthracycline treatment. METHODS AND RESULTS: Large-white male pigs (n=40) were included in different experimental protocols (ExPr.) according to anthracycline cumulative exposure [0.45 mg/kg intracoronary (IC) doxorubicin per injection] and follow-up: control (no doxorubicin); single injection and sacrifice either at 48 h (ExPr. 1) or 2 weeks (ExPr. 2); 3 injections 2 weeks apart (low cumulative dose) and sacrifice either 2 weeks (ExPr. 3) or 12 weeks (ExPr. 4) after third injection; five injections 2 weeks apart (high cumulative dose) and sacrifice 8 weeks after fifth injection (ExPr. 5). All groups were assessed by serial cardiac magnetic resonance (CMR) to quantify perfusion and invasive measurement of coronary flow reserve (CFR). At the end of each protocol, animals were sacrificed for ex vivo analyses. Vascular function was further evaluated by myography in explanted coronary arteries of pigs undergoing ExPr. 3 and controls. A single doxorubicin injection had no impact on microcirculation status, excluding a direct chemical toxicity. A series of five fortnightly doxorubicin injections (high cumulative dose) triggered a progressive decline in microcirculation status, evidenced by reduced CMR-based myocardial perfusion and CFR-measured impaired functional microcirculation. In the high cumulative dose regime (ExPr. 5), microcirculation changes appeared long before any contractile defect became apparent. Low cumulative doxorubicin dose (three bi-weekly injections) was not associated with any contractile defect across long-term follow-up, but provoked persistent microcirculation damage, evident soon after third dose injection. Histological and myograph evaluations confirmed structural damage to arteries of all calibres even in animals undergoing low cumulative dose regimes. Conversely, arteriole damage and capillary bed alteration occurred only after high cumulative dose regime. CONCLUSION: Serial in vivo evaluations of microcirculation status using state-of-the-art CMR and invasive CFR show that anthracyclines treatment is associated with progressive and irreversible damage to the microcirculation. This long-persisting damage is present even in low cumulative dose regimes, which are not associated with cardiac contractile deficits. Microcirculation damage might explain some of the increased incidence of cardiovascular events in cancer survivors who received anthracyclines without showing cardiac contractile defects.

Metoprolol in Critically Ill Patients With COVID-19.

BACKGROUND: Severe coronavirus disease-2019 (COVID-19) can progress to an acute respiratory distress syndrome (ARDS), which involves alveolar infiltration by activated neutrophils. The beta-blocker metoprolol has been shown to ameliorate exacerbated inflammation in the myocardial infarction setting. OBJECTIVES: The purpose of this study was to evaluate the effects of metoprolol on alveolar inflammation and on respiratory function in patients with COVID-19-associated ARDS. METHODS: A total of 20 COVID-19 patients with ARDS on invasive mechanical ventilation were randomized to metoprolol (15 mg daily for 3 days) or control (no treatment). All patients underwent bronchoalveolar lavage (BAL) before and after metoprolol/control. The safety of metoprolol administration was evaluated by invasive hemodynamic and electrocardiogram monitoring and echocardiography. RESULTS: Metoprolol administration was without side effects. At baseline, neutrophil content in BAL did not differ between groups. Conversely, patients randomized to metoprolol had significantly fewer neutrophils in BAL on day 4 (median: 14.3 neutrophils/µl [Q1, Q3: 4.63, 265 neutrophils/µl] vs median: 397 neutrophils/µl [Q1, Q3: 222, 1,346 neutrophils/µl] in the metoprolol and control groups, respectively; P = 0.016). Metoprolol also reduced neutrophil extracellular traps content and other markers of lung inflammation. Oxygenation (PaO2:FiO2) significantly improved after 3 days of metoprolol treatment (median: 130 [Q1, Q3: 110, 162] vs median: 267 [Q1, Q3: 199, 298] at baseline and day 4, respectively; P = 0.003), whereas it remained unchanged in control subjects. Metoprolol-treated patients spent fewer days on invasive mechanical ventilation than those in the control group (15.5 ± 7.6 vs 21.9 ± 12.6 days; P = 0.17). CONCLUSIONS: In this pilot trial, intravenous metoprolol administration to patients with COVID-19-associated ARDS was safe, reduced exacerbated lung inflammation, and improved oxygenation. Repurposing metoprolol for COVID-19-associated ARDS appears to be a safe and inexpensive strategy that can alleviate the burden of the COVID-19 pandemic.

#CienciaenelParlamento: la necesidad de una oficina parlamentaria de asesoramiento científico y tecnológico / #CienciaenelParlamento: the need for a parliamentary office of science and technology advice

Uno de los objetivos de la iniciativa ciudadana #CienciaenelParlamento es contribuir al establecimiento de una oficina parlamentaria de asesoramiento científico y tecnológico en las Cortes Generales. Dicha oficina estaría encargada de favorecer espacios de confluencia entre el conocimiento científico y las políticas públicas, y fomentar el debate entre políticos, expertos y la sociedad en general. En este artículo se revisan los principales mecanismos parlamentarios de asesoramiento científico, con especial atención a uno de ellos: las oficinas parlamentarias de asesoramiento científico y tecnológico. Estas oficinas existen en 22 parlamentos en todo el mundo, pero en España no. En segundo lugar, se describe la acción realizada por #CienciaenelParlamento en su colaboración con el Congreso de los Diputados durante la XII Legislatura, que culminó con unas jornadas en noviembre de 2018 en las que más de 200 científicos y casi 100 diputados debatieron sobre 12 temas de actualidad con el conocimiento científico más actualizado. Gracias a esta colaboración, el Congreso ha dado los primeros pasos para el establecimiento oficial de una oficina de asesoramiento científico. Por último, se exponen algunos ejemplos de cómo la acción de estas oficinas parlamentarias de asesoramiento científico y tecnológico en otros países se imbrica con la de otros agentes para un mayor debate público y la tramitación de mejores políticas públicas en temas de salud y otras áreas. Como conclusión, desde #CienciaenelParlamento creemos que una oficina asesora ayudaría a enriquecer el ecosistema ciencia-política en España. (AU)

One of the aims of the citizen's initiative #CienciaenelParlamento is helping to establishing a parliamentary office of scientific and technological advice in the Spanish parliament. Said office would be in charge of fostering networking spaces between scientific knowledge and public policies and of triggering public debate between policy-makers, experts and the general public. In this article, we first review the main parliamentary mechanisms of scientific advice, with special attention to one in particular: parliamentary offices of scientific and technological advice. These offices exist in 22 parliaments worldwide, but there are none in Spain. Second, we describe the activity undertaken by #CienciaenelParlamento in its collaboration with the Congress of Deputies during the 12th Spanish Legislature. This collaboration reached its peak with a two-day networking event in November 2018 with over 200 scientists and almost 100 deputies, who all debated twelve topics of social interest and the most up-to-date scientific knowledge. Thanks to this collaboration, the Congress has taken the first steps towards officially establishing a parliamentary science advice office. Lastly, we enumerate some examples about how these parliamentary offices in other countries have contributed with other stakeholders to better public debate and processing of public policies in public health and other areas. To conclude, we at #CienciaenelParlamento believe that a parliamentary science advice office would help to enhance the science-policy ecosystem in Spain. (AU)

Recent advances in the pharmacotherapy of pulmonary hypertension: practical considerations.

Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary vascular remodeling leading to increased vascular resistance. The increased afterload contributes to the development of right ventricular dysfunction and heart failure, which is the leading cause of death among patients with PAH. The development of specific treatments has markedly improved the prognosis of this population. However, PAH continues to be an incurable, life­limiting condition, which creates a major burden for healthcare systems. This review describes the currently used treatments for PAH and provides insight into novel therapeutic targets that aim to reduce vascular remodeling, which ultimately leads to right ventricular failure.

[#CienciaenelParlamento: the need for a parliamentary office of science and technology advice]. / #CienciaenelParlamento: la necesidad de una oficina parlamentaria de asesoramiento científico y tecnológico.

One of the aims of the citizen's initiative #CienciaenelParlamento is helping to establishing a parliamentary office of scientific and technological advice in the Spanish parliament. Said office would be in charge of fostering networking spaces between scientific knowledge and public policies and of triggering public debate between policy-makers, experts and the general public. In this article, we first review the main parliamentary mechanisms of scientific advice, with special attention to one in particular: parliamentary offices of scientific and technological advice. These offices exist in 22 parliaments worldwide, but there are none in Spain. Second, we describe the activity undertaken by #CienciaenelParlamento in its collaboration with the Congress of Deputies during the 12th Spanish Legislature. This collaboration reached its peak with a two-day networking event in November 2018 with over 200 scientists and almost 100 deputies, who all debated twelve topics of social interest and the most up-to-date scientific knowledge. Thanks to this collaboration, the Congress has taken the first steps towards officially establishing a parliamentary science advice office. Lastly, we enumerate some examples about how these parliamentary offices in other countries have contributed with other stakeholders to better public debate and processing of public policies in public health and other areas. To conclude, we at #CienciaenelParlamento believe that a parliamentary science advice office would help to enhance the science-policy ecosystem in Spain.

Remote ischaemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity.

AIMS: Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. METHODS AND RESULTS: Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs. CONCLUSION: In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.

The Value of Mouse Models of Rare Diseases: A Spanish Experience.

Animal models are invaluable for biomedical research, especially in the context of rare diseases, which have a very low prevalence and are often complex. Concretely mouse models provide key information on rare disease mechanisms and therapeutic strategies that cannot be obtained by using only alternative methods, and greatly contribute to accelerate the development of new therapeutic options for rare diseases. Despite this, the use of experimental animals remains controversial. The combination of respectful management, ethical laws and transparency regarding animal experimentation contributes to improve society's opinion about biomedical research and positively impacts on research quality, which eventually also benefits patients. Here we present examples of current advances in preclinical research in rare diseases using mouse models, together with our perspective on future directions and challenges.

Metoprolol exerts a non-class effect against ischaemia-reperfusion injury by abrogating exacerbated inflammation.

AIMS: Clinical guidelines recommend early intravenous ß-blockers during ongoing myocardial infarction; however, it is unknown whether all ß-blockers exert a similar cardioprotective effect. We experimentally compared three clinically approved intravenous ß-blockers. METHODS AND RESULTS: Mice undergoing 45 min/24 h ischaemia-reperfusion (I/R) received vehicle, metoprolol, atenolol, or propranolol at min 35. The effect on neutrophil infiltration was tested in three models of exacerbated inflammation. Neutrophil migration was evaluated in vitro and in vivo by intravital microscopy. The effect of ß-blockers on the conformation of the ß1 adrenergic receptor was studied in silico. Of the tested ß-blockers, only metoprolol ameliorated I/R injury [infarct size (IS) = 18.0% ± 0.03% for metoprolol vs. 35.9% ± 0.03% for vehicle; P < 0.01]. Atenolol and propranolol had no effect on IS. In the three exacerbated inflammation models, neutrophil infiltration was significantly attenuated only in the presence of metoprolol (60%, 50%, and 70% reductions vs. vehicle in myocardial I/R injury, thioglycolate-induced peritonitis, and lipopolysaccharide-induced acute lung injury, respectively). Migration studies confirmed the particular ability of metoprolol to disrupt neutrophil dynamics. In silico analysis indicated different intracellular ß1 adrenergic receptor conformational changes when bound to metoprolol than to the other two ß-blockers. CONCLUSIONS: Metoprolol exerts a disruptive action on neutrophil dynamics during exacerbated inflammation, resulting in an infarct-limiting effect not observed with atenolol or propranolol. The differential effect of ß-blockers may be related to distinct conformational changes in the ß1 adrenergic receptor upon metoprolol binding. If these data are confirmed in a clinical trial, metoprolol should become the intravenous ß-blocker of choice for patients with ongoing infarction.

Effect of Coronavirus Disease 2019 in Pulmonary Circulation. The Particular Scenario of Precapillary Pulmonary Hypertension.

The Coronavirus Disease of 2019 (COVID-19) has supposed a global health emergency affecting millions of people, with particular severity in the elderly and patients with previous comorbidities, especially those with cardiovascular disease. Patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) could represent an especially vulnerable population because of the high mortality rates reported for respiratory infections. However, the number of COVID-19 cases reported among PAH and CTEPH patients is surprisingly low. Furthermore, the clinical picture that has been described in these patients is far from the severity that experts would expect. Endothelial dysfunction is a common feature between patients with PAH/CTEPH and COVID-19, leading to ventilation/perfusion mismatch, vasoconstriction, thrombosis and inflammation. In this picture, the angiotensin-converting enzyme 2 plays an essential role, being directly involved in the pathophysiology of both clinical entities. Some of these common characteristics could explain the good adaptation of PAH and CTEPH patients to COVID-19, who could also have obtained a benefit from the disease's specific treatments (anticoagulant and pulmonary vasodilators), probably due to its protective effect on the endothelium. Additionally, these common features could also lead to PAH/CTEPH as a potential sequelae of COVID-19. Throughout this comprehensive review, we describe the similarities and differences between both conditions and the possible pathophysiological and therapeutic-based mechanisms leading to the low incidence and severity of COVID-19 reported in PAH/CTEPH patients to date. Nevertheless, international registries should look carefully into this population for better understanding and management.

Pharmacology of Pulmonary Arterial Hypertension: An Overview of Current and Emerging Therapies.

Pulmonary arterial hypertension is a rare and devastating disease characterized by an abnormal chronic increase in pulmonary arterial pressure above 20 mmHg at rest, with a poor prognosis if not treated. Currently, there is not a single fully effective therapy, even though a dozen of drugs have been developed in the last decades. Pulmonary arterial hypertension is a multifactorial disease, meaning that several molecular mechanisms are implicated in its pathology. The main molecular pathways regulating the pulmonary vasomotor tone-endothelin, nitric oxide, and prostacyclin-are the most biologically and therapeutically explored to date. However, drugs targeting these pathways have already found their limitations. In the last years, translational research and clinical trials have made a strong effort in suggesting and testing novel therapeutic strategies for this disease. These approaches involve targeting the main molecular pathways with novel drugs, drug repurposing for novel targets, and also using combinatorial therapies. In this review, we summarize current strategies and drugs targeting the endothelin, nitric oxide, and prostacyclin pathways, as well as, the emerging new drugs proposed to cope with vascular remodelling, metabolic switch, perivascular inflammation, epigenetic modifications, estrogen deregulation, serotonin, and other neurohumoral mechanisms characteristic of this disease. Nowadays, pulmonary arterial hypertension remains an incurable disease; however, the incoming new knowledge makes us believe that new promising therapies are coming to the clinical arena soon.