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Special Issue "Novel Molecular Targets for Cardioprotection: The EU-CARDIOPROTECTION COST Action (CA16225)"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2018)

Special Issue Editors

Guest Editor
Prof. Dr. Ioanna Andreadou

Laboratory of Pharmacology, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
Website | E-Mail
Interests: cardiovascular pharmacology and toxicology; myocardial ischemic pre- and postconditioning (cardioprotection); oxidative stress in ischemia – reperfusion injury; molecular toxicology
Guest Editor
Prof. Derek J Hausenloy

1. Signature Research Program in Cardiovascular & Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
2. The Hatter Cardiovascular Institute,Institute of Cardiovascular Sciences, University College London, 67 Chenies Mews, London WC1E 6HX, UK
Website | E-Mail
Phone: +(44) 203-447-9888
Interests: cardioprotection; myocardial ischemic preconditioning and postconditioning; ischemia-reperfusion injury; mitochondria as targets for cardioprotection; remote ischemic conditioning
Co-Guest Editor
Dr. Hector A. Cabrera Fuentes

Institute for Biochemistry, Medical Faculty, Justus-Liebig-University, Friedrichstrasse 24, D-35392 Giessen, Germany
E-Mail
Interests: Basic science and clinical research in organ protection against acute ischaemia/reperfudion injury with a special focus on cardiac protection and acute inflammation and remodeling; basic science and translational research in atherosclerosis and chronic inflammation processes

Special Issue Information

Dear Colleagues,

Ischemic heart disease (IHD) is a leading cause of death and disability worldwide. Despite intensive experimental research over the last three to four decades, there is currently no effective therapy for protecting the heart following acute myocardial infarction in order to prevent heart failure—termed cardioprotection. Therefore, novel molecular targets for cardioprotection need to be discovered in order to improve clinical outcomes of IHD patients. This is the overall objective of our newly established EU-CARDIOPROTECTION COST Action (CA16225 http://www.cardioprotection.eu/), which comprises a European network of 100 leading cardioprotection researchers, dedicated to realising the therapeutic potential of novel cardioprotective therapies for patient benefit. This will be achieved through the discovery of novel therapeutic targets and strategies for cardioprotection (such as combination multi-targeted therapies), and investigating the confounding effects of co-morbidities and co-medication on cardioprotection.

Therefore, in this Special Issue of IJMS, we invite you to submit both review and original pre-clinical articles on the topic of cardioprotection with a special focus on novel molecular targets for cardioprotection.

Dr. Ioanna Andreadou
Prof. Derek J Hausenloy
Guest Editors
Dr. Hector A. Cabrera Fuentes
Co-Guest Editor

EU-CARDIOPROTECTION COST Action: CA16225 http://www.cardioprotection.eu/

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Manuscript Submission Information

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Keywords

  • Mitochondria
  • Reactive oxygen species
  • Cyotprotective signaling pathways
  • Cardioprotection
  • Ischemia-Reperfusion injury
  • Acute myocardial infarction
  • Ischemic preconditioning
  • Ischemic postconditioning
  • Remote ischemic conditioning

Published Papers (9 papers)

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Research

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Open AccessArticle Transcriptional Alterations by Ischaemic Postconditioning in a Pig Infarction Model: Impact on Microvascular Protection
Int. J. Mol. Sci. 2019, 20(2), 344; https://doi.org/10.3390/ijms20020344
Received: 30 November 2018 / Revised: 4 January 2019 / Accepted: 8 January 2019 / Published: 15 January 2019
PDF Full-text (894 KB)
Abstract
Although the application of cardioprotective ischaemia/reperfusion (I/R) stimuli after myocardial infarction (MI) is a promising concept for salvaging the myocardium, translation to a clinical scenario has not fulfilled expectations. We have previously shown that in pigs, ischaemic postconditioning (IPostC) reduces myocardial oedema and
[...] Read more.
Although the application of cardioprotective ischaemia/reperfusion (I/R) stimuli after myocardial infarction (MI) is a promising concept for salvaging the myocardium, translation to a clinical scenario has not fulfilled expectations. We have previously shown that in pigs, ischaemic postconditioning (IPostC) reduces myocardial oedema and microvascular obstruction (MVO), without influencing myocardial infarct size. In the present study, we analyzed the mechanisms underlying the IPostC-induced microvascular protection by transcriptomic analysis, followed by pathway analysis. Closed-chest reperfused MI was induced by 90 min percutaneous balloon occlusion of the left anterior descending coronary artery, followed by balloon deflation in anaesthetised pigs. Animals were randomised to IPostC (n = 8), MI (non-conditioned, n = 8), or Control (sham-operated, n = 4) groups. After three hours or three days follow-up, myocardial tissue samples were harvested and subjected to RNA-seq analysis. Although the transcriptome analysis revealed similar expression between IPostC and MI in transcripts involved in cardioprotective pathways, we identified gene expression changes responding to IPostC at the three days follow-up. Focal adhesion signaling, downregulated genes participating in cardiomyopathy and activation of blood cells may have critical consequences for microvascular protection. Specific analyses of the gene subsets enriched in the endothelium of the infarcted area, revealed strong deregulation of transcriptional functional clusters, DNA processing, replication and repair, cell proliferation, and focal adhesion, suggesting sustentative function in the endothelial cell layer protection and integrity. The spatial and time-dependent transcriptome analysis of porcine myocardium supports a protective effect of IPostC on coronary microvasculature post-MI. Full article
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Open AccessArticle Sevoflurane, Propofol and Carvedilol Block Myocardial Protection by Limb Remote Ischemic Preconditioning
Int. J. Mol. Sci. 2019, 20(2), 269; https://doi.org/10.3390/ijms20020269
Received: 8 November 2018 / Revised: 4 January 2019 / Accepted: 8 January 2019 / Published: 11 January 2019
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Abstract
The effects of remote ischemic preconditioning (RIPC) in cardiac surgery have been inconsistent. We investigated whether anesthesia or beta-blockers interfere with RIPC cardioprotection. Fifty patients undergoing cardiac surgery were randomized to receive limb RIPC (four cycles of 5-min of upper arm cuff inflation/deflation)
[...] Read more.
The effects of remote ischemic preconditioning (RIPC) in cardiac surgery have been inconsistent. We investigated whether anesthesia or beta-blockers interfere with RIPC cardioprotection. Fifty patients undergoing cardiac surgery were randomized to receive limb RIPC (four cycles of 5-min of upper arm cuff inflation/deflation) in the awake state (no-anesthesia; n = 17), or under sevoflurane (n = 17) or propofol (n = 16) anesthesia. In a separate crossover study, 11 healthy volunteers received either carvedilol or no medication prior to RIPC. Plasma dialysates were obtained and perfused through an isolated male Sprague–Dawley rat heart subjected to 30-min ischemia/60-min reperfusion, following which myocardial infarct (MI) size was determined. In the cardiac surgery study, pre-RIPC MI sizes were similar among the groups (39.7 ± 4.5% no-anesthesia, 38.9 ± 5.3% sevoflurane, and 38.6 ± 3.6% propofol). However, post-RIPC MI size was reduced in the no-anesthesia group (27.5 ± 8.0%; p < 0.001), but not in the anesthesia groups (35.7 ± 6.9% sevoflurane and 35.8 ± 5.8% propofol). In the healthy volunteer study, there was a reduction in MI size with RIPC in the no-carvedilol group (41.7 ± 4.3% to 30.6 ± 8.5%; p < 0.0001), but not in the carvedilol group (41.0 ± 4.0% to 39.6 ± 5.6%; p = 0.452). We found that the cardioprotective effects of limb RIPC were abolished under propofol or sevoflurane anesthesia and in the presence of carvedilol therapy. Full article
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Open AccessArticle Novel Potentials of the DPP-4 Inhibitor Sitagliptin against Ischemia-Reperfusion (I/R) Injury in Rat Ex-Vivo Heart Model
Int. J. Mol. Sci. 2018, 19(10), 3226; https://doi.org/10.3390/ijms19103226
Received: 3 July 2018 / Revised: 12 October 2018 / Accepted: 15 October 2018 / Published: 18 October 2018
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Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral anti-diabetic drugs, implicated in pleiotropic secondary cardioprotective effects. The aim of the study was to unveil the unknown and possible cardioprotective targets that can be exerted by sitagliptin (Sitg) against ischemia-reperfusion (I/R) injury. Male
[...] Read more.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral anti-diabetic drugs, implicated in pleiotropic secondary cardioprotective effects. The aim of the study was to unveil the unknown and possible cardioprotective targets that can be exerted by sitagliptin (Sitg) against ischemia-reperfusion (I/R) injury. Male wistar rats received 2 weeks’ Sitg oral treatment of different doses (25, 50, 100, and 150 mg/kg/day), or saline as a Control. Hearts were then isolated and subjected to two different I/R injury protocols: 10 min perfusion, 45 min regional ischemia, and 120 min reperfusion for infarct size (IS) measurement, or: 10 min perfusion, 45 min regional ischemia and 10 min reperfusion for biochemical analysis: nitric oxide synthases (NOSs) and DPP-4 activity, glucagon-like peptide-1 (GLP-1), Calcium, transient receptor potential vanilloid (TRPV)-1 and calcitonin gene-related peptide (CGRP) levels, transient receptor potential canonical (TRPC)-1 and e-NOS protein expression. NOS inhibitor (l-NAME) and TRPV-1 inhibitor (Capsazepine) were utilized to confirm the implication of both signaling mechanisms in DPP-4 inhibition-induced at the level of IS. Findings show that Sitg (50 mg) resulted in significant decrease in IS and DPP-4 activity, and significant increase in GLP-1, NOS activity, e-NOS expression, TRPV-1 level and TRPC-1 expression, compared to controls. Results of CGRP are in line with TRPV-1, as a downstream regulatory effect. NOS system and transient receptor potential (TRP) channels can contribute to DPP-4 inhibition-mediated cardioprotection against I/R injury using Sitagliptin. Full article
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Open AccessArticle Upregulation of Myocardial and Vascular Phosphodiesterase 9A in A Model of Atherosclerotic Cardiovascular Disease
Int. J. Mol. Sci. 2018, 19(10), 2882; https://doi.org/10.3390/ijms19102882
Received: 7 August 2018 / Revised: 10 September 2018 / Accepted: 20 September 2018 / Published: 22 September 2018
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Abstract
Atherosclerosis is strongly associated with cardiac dysfunction and heart failure. Besides microvascular dysfunction and diminishment of the cardiac nitric oxide-Protein Kinase G (NO-PKG) pathway, recent evidence suggests that phosphodiesterase 9A (PDE9A) enzyme has an unfavorable role in pathological changes. Here, we characterized a
[...] Read more.
Atherosclerosis is strongly associated with cardiac dysfunction and heart failure. Besides microvascular dysfunction and diminishment of the cardiac nitric oxide-Protein Kinase G (NO-PKG) pathway, recent evidence suggests that phosphodiesterase 9A (PDE9A) enzyme has an unfavorable role in pathological changes. Here, we characterized a rabbit model that shows cardiac dysfunction as a result of an atherogenic diet, and examined the myocardial PDE9A signaling. Rabbits were divided into Control (normal diet) and HC (atherogenic diet) groups. Cardiac function was evaluated by echocardiography. Vascular function was assessed, along with serum biomarkers. Histological stains were conducted, expression of selected proteins and cyclic guanosine monophosphate (cGMP) levels were determined. Signs of diastolic dysfunction were shown in HC animals, along with concentric hypertrophy and interstitial fibrosis. Endothelial function was diminished in HC rabbits, along with marked reduction in the aortic lumen, and increased left ventricle outflow tract (LVOT) pressures. A significant increase was shown in myocardial PDE9A levels in HC animals with unchanged vasodilator-stimulated phosphoprotein (VASP) phosphorylation and cGMP levels. Upregulation of PDE9A may be associated with early stage of cardiac dysfunction in atherosclerotic conditions. Since PDE9A is involved in cGMP degradation and in deactivation of the cardioprotective PKG signaling pathway, it may become an encouraging target for future investigations in atherosclerotic diseases. Full article
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Open AccessArticle F13A1 Gene Variant (V34L) and Residual Circulating FXIIIA Levels Predict Short- and Long-Term Mortality in Acute Myocardial Infarction after Coronary Angioplasty
Int. J. Mol. Sci. 2018, 19(9), 2766; https://doi.org/10.3390/ijms19092766
Received: 13 August 2018 / Revised: 10 September 2018 / Accepted: 11 September 2018 / Published: 14 September 2018
Cited by 1 | PDF Full-text (2770 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Factor XIIIA (FXIIIA) levels are independent predictors of early prognosis after acute myocardial infarction (AMI) and the Valine-to-Leucine (V34L) single nucleotide polymorphism (SNP) seems associated with lower AMI risk. Since the long-term AMI prognosis merits deeper investigation, we performed an observational study evaluating
[...] Read more.
Factor XIIIA (FXIIIA) levels are independent predictors of early prognosis after acute myocardial infarction (AMI) and the Valine-to-Leucine (V34L) single nucleotide polymorphism (SNP) seems associated with lower AMI risk. Since the long-term AMI prognosis merits deeper investigation, we performed an observational study evaluating relationships between FXIIIA residual levels, cardiovascular risk-factors, and inherited genetic predispositions. FXIIIA V34L was genotyped in 333 AMI patients and a five-year follow-up was performed. FXIIIA levels assessed at day-zero (d0) and four days after AMI (d4), and conventional risk factors were analyzed, focusing on the development of major adverse cardiovascular events (MACE). FXIIIA assessed at d0 and d4 was also an independent MACE predictor in the long-term follow-up (FXIIIAd0, Odds Ratio (OR) = 3.02, 1.79–5.1, p = 0.013; FXIIIAd4, OR = 4.46, 2.33–8.55, p = 0.0001). FXIIIAd4 showed the strongest MACE association, suggesting that the FXIIIA protective role is maximized when high levels are maintained for longer time. Conversely, FXIIIA levels stratified by V34L predicted MACE at a lesser extent among L34-carriers (Hazard Risk (HR)VV34 = 3.89, 2.19–6.87, p = 0.000003; HRL34-carriers = 2.78, 1.39–5.57, p = 0.0039), and V34L did not predict all MACE, only multiple-MACE occurrence (p = 0.0087). Finally, in survival analysis, heart failure and death differed significantly from stroke and recurrent ischemia (p = 0.0013), with FXIIIA levels appreciably lower in the former (p = 0.05). Overall, genetically-determined FXIIIA levels have a significant long-term prognostic role, suggesting that a pharmacogenetics approach might help to select those AMI patients at risk of poor prognosis in the need of dedicated treatments. Full article
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Review

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Open AccessReview The Role of O-GlcNAcylation for Protection against Ischemia-Reperfusion Injury
Int. J. Mol. Sci. 2019, 20(2), 404; https://doi.org/10.3390/ijms20020404
Received: 30 November 2018 / Revised: 12 January 2019 / Accepted: 15 January 2019 / Published: 18 January 2019
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Abstract
Ischemia reperfusion injury (IR injury) associated with ischemic heart disease contributes significantly to morbidity and mortality. O-linked β-N-acetylglucosamine (O-GlcNAc) is a dynamic posttranslational modification that plays an important role in numerous biological processes, both in normal cell functions and disease. O-GlcNAc increases in
[...] Read more.
Ischemia reperfusion injury (IR injury) associated with ischemic heart disease contributes significantly to morbidity and mortality. O-linked β-N-acetylglucosamine (O-GlcNAc) is a dynamic posttranslational modification that plays an important role in numerous biological processes, both in normal cell functions and disease. O-GlcNAc increases in response to stress. This increase mediates stress tolerance and cell survival, and is protective. Increasing O-GlcNAc is protective against IR injury. Experimental cellular and animal models, and also human studies, have demonstrated that protection against IR injury by ischemic preconditioning, and the more clinically applicable remote ischemic preconditioning, is associated with increases in O-GlcNAc levels. In this review we discuss how the principal mechanisms underlying tissue protection against IR injury and the associated immediate elevation of O-GlcNAc may involve attenuation of calcium overload, attenuation of mitochondrial permeability transition pore opening, reduction of endoplasmic reticulum stress, modification of inflammatory and heat shock responses, and interference with established cardioprotective pathways. O-GlcNAcylation seems to be an inherent adaptive cytoprotective response to IR injury that is activated by mechanical conditioning strategies. Full article
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Open AccessReview New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease
Int. J. Mol. Sci. 2019, 20(1), 187; https://doi.org/10.3390/ijms20010187
Received: 2 December 2018 / Revised: 27 December 2018 / Accepted: 28 December 2018 / Published: 7 January 2019
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Abstract
The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of
[...] Read more.
The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even “uncoupling” of the enzyme by adverse regulation of well-defined “redox switches” in eNOS itself or up-/down-stream signaling molecules. Of note, not only eNOS function and activity in the endothelium are essential for vascular integrity and homeostasis, but also eNOS in perivascular adipose tissue plays an important role for these processes. Accordingly, eNOS protein represents an attractive therapeutic target that, so far, was not pharmacologically exploited. With our present work, we want to provide an overview on recent advances and future therapeutic strategies that could be used to target eNOS activity and function in cardiovascular (and other) diseases, including life style changes and epigenetic modulations. We highlight the redox-regulatory mechanisms in eNOS function and up- and down-stream signaling pathways (e.g., tetrahydrobiopterin metabolism and soluble guanylyl cyclase/cGMP pathway) and their potential pharmacological exploitation. Full article
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Open AccessReview Beyond a Measure of Liver Function—Bilirubin Acts as a Potential Cardiovascular Protector in Chronic Kidney Disease Patients
Int. J. Mol. Sci. 2019, 20(1), 117; https://doi.org/10.3390/ijms20010117
Received: 28 November 2018 / Revised: 17 December 2018 / Accepted: 21 December 2018 / Published: 29 December 2018
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Abstract
Bilirubin is a well-known neurotoxin in newborn infants; however, current evidence has shown that a higher serum bilirubin concentration in physiological ranges is associated with a lower risk for the development and progression of both chronic kidney disease (CKD) and cardiovascular disease (CVD)
[...] Read more.
Bilirubin is a well-known neurotoxin in newborn infants; however, current evidence has shown that a higher serum bilirubin concentration in physiological ranges is associated with a lower risk for the development and progression of both chronic kidney disease (CKD) and cardiovascular disease (CVD) in adults. The protective mechanisms of bilirubin in CVD, CKD, and associated mortality may be ascribed to its antioxidant and anti-inflammatory properties. Bilirubin further improves insulin sensitivity, reduces low-density lipoprotein cholesterol levels and inhibits platelet activation in at-risk individuals. These effects are expected to maintain normal vascular homeostasis and thus reduce the incidence of CKD and the risks of cardiovascular complications and death. In this review, we highlight the recent advances in the biological actions of bilirubin in the pathogenesis of CVD and CKD progression, and further propose that targeting bilirubin metabolism could be a potential approach to ameliorate morbidity and mortality in CKD patients. Full article
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Open AccessReview Temporal Frame of Immune Cell Infiltration during Heart Failure Establishment: Lessons from Animal Models
Int. J. Mol. Sci. 2018, 19(12), 3719; https://doi.org/10.3390/ijms19123719
Received: 6 October 2018 / Revised: 13 November 2018 / Accepted: 14 November 2018 / Published: 22 November 2018
PDF Full-text (1667 KB) | HTML Full-text | XML Full-text
Abstract
Heart failure (HF) is a cardiovascular syndrome characterized by maladaptive changes with an underlying inflammatory mediated pathogenesis. Nevertheless, current therapy is aimed at the heart workload and neurohormonal axis; thus, prognosis remains poor. To continue improving treatment, we rely on murine models for
[...] Read more.
Heart failure (HF) is a cardiovascular syndrome characterized by maladaptive changes with an underlying inflammatory mediated pathogenesis. Nevertheless, current therapy is aimed at the heart workload and neurohormonal axis; thus, prognosis remains poor. To continue improving treatment, we rely on murine models for a better understanding of HF pathophysiology. Among them, pressure overload HF (PO-HF) animal models are a common strategy. Development of PO-HF is characterized by monocyte infiltration, which orchestrates a cascade of events leading to sustained inflammation and maladaptive changes. Here, we divide the PO-HF model progression into four phases and describe the inflammatory, structural, and gene expression profiles. This division is relevant due to its similarities with clinical hypertensive heart disease progression to HF. Evidence shows improvement in hemodynamic and other local parameters by altering the inflammatory response in a specific immune response at a specific point of time. Thus, it is relevant to focus on the time-dependent immune response interaction in order to provide more effective therapy. This review summarizes the pathogenesis of PO-HF murine models, highlighting the inflammatory events in a time frame view. By this approach, we expect to provide researchers with a better understanding of the intertwining time-dependent events that occur in PO-HF. Full article
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