Research Gilles De Keulenaer

Abstract

Heart failure (HF) and cancer are the two most common causes of death. An increasing number of patients suffer from both diseases. In the past, their occurrence in the same patients was exclusively attributed to shared risk factors, e.g. smoking. Recent studies have demonstrated that HF directly stimulates cancer growth in different mouse models of HF and cancer, but the underlying mechanisms are incompletely understood. An important unanswered question is whether treating HF with available therapy affect cancer progression. First, I will test the effects of currently used HF treatments in a mouse model of HF and solid cancer. I expect that specific HF therapies will slow HF-enhanced cancer growth. Second, I will test the same treatments in a mouse model of HF and spontaneously metastatic cancer. The comparison of the effects of HF treatments on solid and metastatic tumors will help to test the central hypothesis; it will provide clinicians with useful insights to select therapies for their patients, but will also be relevant to individuate the pathways involved in HF-enhanced cancer growth. Third, I will perform single-nuclei RNA sequencing of both tumors and myocardium. These experiments will reveal the underlying mechanisms linking HF to cancer thanks to the identification of receptors present on both tissues. The ultimate goal would be the identification of novel therapeutic targets, potentially helping millions of patients.

Researcher(s)

• Promoter: Segers Vincent
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Van Laere Steven
• Fellow: Civati Celine

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Despite recent therapeutic advances, chronic heart failure (CHF) remains a common and fatal condition. Patients with CHF often have severe symptoms that limit their daily activity and result in a poor quality-of-life. New therapeutic strategies, based on new targets are needed. The signaling pathway consisting of neureguline-1 (NRG1) and its tyrosine kinase receptor ERBB4 could represent such a new target because of its pleiotropic profile and its crucial role in cardiac (patho)physiology. Therapies with recombinant NRG1 are being tested in clinical trials, in which NRG1 is administered intravenously in hospital. This project is based on the premise that small-molecule ERBB4 agonists could be more efficacious in chronic treatment regimens. Therefore, we started a FWO-funded project in 2018 with a high-throughput screening (HTS), resulting in the identification of 8 first-generation ERBB4 agonists that showed ERBB4-specificity and induced antifibrotic effects, but the potency and efficacy compared to NRG1 was relatively low. Recently, in collaboration with the European Lead Factory, we conducted an ultraHTS resulting in 7 structurally unrelated "second-generation" compounds, which are up to a 1000-fold more potent than the first-generation compounds at receptor level. Herein, we propose to study the biological effects of these ERBB4 agonists with the aim to increase our understanding of the cardiac ERBB system and to develop new HF therapies.

Researcher(s)

• Promoter: Segers Vincent
• Co-promoter: De Keulenaer Gilles
• Fellow: Cools Julie

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

The Vevo LAZR-X is an imaging platform for preclinical applications capable of acquiring in vivo anatomical, functional and molecular data. It combines ultra high frequency ultrasound with photoacoustic imaging (a new biomedical imaging modality based on the use of lasergenerated ultrasound) for high resolution images as well as software for analysis and quantification. This equipment will be used in the context of the study of (cardio)vascular diseases, genetics of the heart, heart valves and aortic dissection, kidney diseases and their effects on the heart and blood vessels, and for cancer research.

Researcher(s)

• Promoter: De Meyer Guido
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Heidbuchel Hein
• Co-promoter: Loeys Bart
• Co-promoter: Smits Evelien
• Co-promoter: Van Craenenbroeck Emeline
• Co-promoter: Verhulst Anja
• Co-promoter: Verstraeten Aline

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Atrial fibrillation (AF) is the most common arrhythmia and a common cause of stroke, heart failure, and death. AF is induced by structural remodeling of the atria, also called atrial myopathy. Current therapy is limited to antiarrhythmic drugs and ablations, but these do not cure the disease. Since atrial myopathy is incompletely understood, we aim to define the molecular, cellular, and structural changes in atrial myopathy. To this end, we will use single-cell RNA sequencing and high-resolution microscopy on a pig model and on human atrial tissues. To integrate these diverse data sets and test their relationships in atrial myopathy that predisposes the tissue to AF, mathematical modelling approaches will be employed. Collectively, these versatile models will create a highly anticipated foundation for various applications, stretching from disease modeling to testing novel strategies for development of curative therapies for an ever-growing group of patients with AF.

Researcher(s)

• Promoter: Heidbuchel Hein
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Segers Vincent

Research team(s)

• Cardiovascular diseases (CARDIOVASC)

Project type(s)

• Research Project

Abstract

Cardiovascular disease and cancer, the two most prevalent causes of death, share pathophysiological mechanisms. In this project we search for a specific molecular mechanism to explain why cancer progresses faster in the presence of heart failure. We hypothesize that the endothelium (the inner lining of heart and blood vessels) secretes a growth factor that binds to receptors expressed by tumors. These studies will be performed in mice that suffer from both heart failure and cancer.

Researcher(s)

• Promoter: De Keulenaer Gilles

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

It has been recently discovered that activation of ErbB2 receptor signaling in cardiac muscle is a physiological response of the heart to cope with overload and injury, and may even lead to cardiac regeneration. Researchers try to translate these findings into pharmacological applications, which would be a significant contribution to clinical cardiology. To date, the easiest way to activate ErbB2 in the heart is treatment with neuregulin-1, a protein growth factor activating ErbB3 and ErbB4, both co-receptors of ErbB2. However, treatment with neuregulin-1 has disadvantages, and there is a need for the development of small chemical molecules, replacing neuregulin-1. This development is starting, but fundamental questions remain. Most importantly, the differential role of ErbB3 or ErbB4 receptors in the different cell types of the heart remains unclear. Based on previous research in our laboratory, we believe that activation of ErbB4 is indispensable for the effects of neuregulin-1 in the heart, both in myocytes and non-myocytes of the cardiac muscle. In this project we test the hypothesis that genetic deletion of ErbB4 in non-myocytes of rodent models makes heart failure a more aggressive disease and attenuates the pharmacological effects of neuregulin-1 in heart failure. If this hypothesis is true, it underscores pharmacological development of chemical agonists of ErbB4 to treat cardiac diseases, and better defines their working mechanism.

Researcher(s)

• Promoter: De Keulenaer Gilles

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and one of the most common causes of stroke and heart failure. AF is induced by electrical, contractile, and structural remodeling of the atria. Moreover, AF itself induces these changes, leading to a vicious circle ("AF begets AF"). Tissue inflammation and fibrosis play an important role in the structural changes, and form the basis of subsequent electrical and contractile atrial dysfunction. Current therapy is limited to rhythm control using antiarrhythmic drugs, but these drugs do not target the structural problem. That may explain why they are only marginally effective. Ablation by electrical isolation of the pulmonary veins (PVI) has broadened the medical opportunities, but it is also unsatisfactory since it addresses only part of the atria. This explains the high relapse rate in patients with more widespread atrial disease (and more persistent forms of AF). More extensive ablations have not shown better results, as can be anticipated by the fact that more destruction will not solve a primarily structural problem. There is a clear medical need for a treatment targeting the underlying pathophysiology leading to structural atrial remodeling. In this project, we will test the hypothesis that the neuregulin-1 (NRG-1)/ErbB pathway is an inhibitory pathway in development of atrial fibrillation. NRG-1 is a member of the epidermal growth factor family that binds to tyrosine kinase receptors and has cell protective and regenerative properties in the heart during heart failure. We recently discovered that NRG-1 has anti-inflammatory and anti-fibrotic properties in different organs, including the heart. As mentioned, fibrosis and inflammation are the main features of structural atrial remodeling present in AF. We hypothesize that (1) the endothelium-derived NRG-1 – ErbB4 system is activated in atrial tissue of patients with atrial fibrillation. We will harvest atrial tissue samples during cardiac surgery procedures from patients with and without AF and determine expression of NRG-1 and its receptors by histology. We will determine (2) whether NRG-1 attenuates atrial fibrosis and atrial fibrillation in two mouse models of atrial fibrillation. For this aim we will use transgenic mouse models that spontaneously develop atrial fibrosis and AF. We will treat these mice with different doses of NRG-1, continuously monitor cardiac rhythm and function, and evaluate histological changes in atria after 4 weeks of treatment. We will (3) develop a sterile pericarditis large animal model of AF in pigs. We will fully characterize reprogramming of different atrial cell types by RNA sequencing. Finally, we will determine (4) whether NRG-1 attenuates atrial fibrosis and atrial fibrillation in these pigs. If successful, this project could open new avenues for treatment of atrial fibrillation by addressing atrial tissue remodeling.

Researcher(s)

• Promoter: Heidbuchel Hein
• Co-promoter: De Keulenaer Gilles
• Co-promoter: De Meyer Guido

Research team(s)

• Cardiovascular diseases (CARDIOVASC)

Project type(s)

• Research Project

Abstract

A disturbed maternal metabolism like in obesity or type II diabetes has clearly been associated with disappointing fertility. We extensively showed that such metabolic disorders have direct effects on the micro-environment of the growing and maturing oocyte, ultimately leading to reduced oocyte and embryo quality. Obesity is a global health threatening problem and recent studies indicated that maternal obesity may result in significant health issues in the offspring. More in depth mechanistic research clearly pointed out the importance of uterine programming in early pregnancy. It is not known however whether the metabolic status of obesity as such and/or potential direct effects of the typical fat rich western type diet are responsible for these observations. Based on the epidemiological relevance of obesity and hypercholesterolemia we hypothesize that obesity or an obesogenic diet of the mother around conception or during the entire pregnancy will alter the micro-environment of the growing embryo and fetus. This will change uterine programming ultimately leading to compromised offspring's health and reproductive physiology. To systematically investigate this hypothesis, we will feed female LDLR knock-out mice (LDLR-/-) an obesogenic diet A) several weeks before conception resulting in maternal obesity at conception or B) solely around conception or C) throughout the entire pregnancy. The offspring will be cross-fostered upon birth and will be used to study the general health of the offspring, the ovarian follicular reserve and the process of folliculo- and oogenesis, the offspring's pre-implantation embryo physiology and gene expression pattern and the receptivity of the offspring's uterus to support full pregnancy resulting in healthy offspring. By using this strategic experimental model we will be able to find the most sensitive window during pregnancy for uterine programming of reproduction, and it allows us to study the effects on every specific step on reproductive functioning. We believe that this project proposal may significantly contribute to the concept of "Developmental Origin of Health and Fertility" by further spreading the knowledge that epigenetic effects of maternal metabolism and diet may jeopardize health but also fertility in the offspring.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Marei Waleed
• Fellow: Moorkens Kerlijne

Research team(s)

• Veterinary physiology and biochemistry

Project website

Project type(s)

• Research Project

Abstract

Neuregulin-1 (NRG-1) is the natural paracrine agonist of the ErbB4 receptor. There is overwhelming evidence that the cardiac NRG-1/ErbB4 system is activated in chronic heart failure (CHF), exerting disease mitigating and regenerative effects. Based on these data from both animals and humans, NRG-1 is developed as a drug for CHF. Clinical trials are performed, and have progressed to stage III (NCT01251406, NCT1214096, and NCT01541202). In addition, there is solid evidence from animals studies that the NRG-1/ErbB4 pathway is involved in other chronic diseases, such as diabetic nephropathy, pulmonary hypertension, atherosclerosis and fibrotic disorders. All of these are common chronic disorders, and potential therapeutic targets for NRG-1. To date, the only way to activate the NRG-1/ErbB4 pathway in vivo is to inject recombinant NRG-1 (rhNRG-1) intravenously. In clinical trials, this is performed over the course of 6-8 hours, which limits applicability of rhNRG-1 in chronic disorders. A small molecule, acting as an ErbB4 agonist would circumvent the drawbacks of a recombinant protein and might be more efficacious in treatment of chronic diseases. Currently, there are no small molecule agonists of ErbB4 identified. In this project, we propose a multi-disciplinary project, including a high throughput experiment using a chemical library to identify agonists of the ErbB4 receptor (OBJECTIVE 1), to test the compound with the highest potency and receptor specificity in validated rodent models of CHF (OBJECTIVE 2), and to define specific patient populations in the heterogeneous field of cardiovascular diseases that could benefit from ErbB4 agonists by quantifying serum levels of neuregulin-1 in human patients (OBJECTIVE 3).

Researcher(s)

• Promoter: De Keulenaer Gilles
• Co-promoter: Segers Vincent

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Neuregulin-1 (NRG-1) is the natural agonist of the ErbB4 receptor. Recent evidence clearly shows that the NRG-1/ErbB4 system has protective effects in various chronic disorders including chronic heart failure, chronic diabetic kidney injury, and fibrotic disorders, such as lung fibrosis. All of these are common and deadly disorders. Recombinant Neuregulin-1 is currently tested in phase 3 clinical trials for the treatment of chronic heart failure. However, recombinant NRG-1 has to be injected intravenously in the hospital over the course of 6-8 hours, which is an issue that severely limits applicability of recombinant NRG-1 in chronic disorders. A small molecule that can act as an ErbB4 agonist could circumvent the drawbacks of a recombinant protein and might be more efficacious in treatment of chronic diseases. Currently, there are no small molecule agonists of ErbB4 identified. In this project, we propose a high throughput experiment using a chemical library to identify agonists of the ErbB4 receptor. After in-house optimization of the assay, we will screen a chemical Library consisting of 20.000 compounds at the VIB Compound Screening Facility. Solubility and receptor specificity for ErbB1, ErbB3, and ErbB4 of the hits of this screening assay will be further evaluated using western blotting and ELISA assays. We will test the compound with the highest potency and receptor specificity in validated rodent models of heart failure and fibrosis. We used these animal models before in our laboratory and we successfully showed protective effects of recombinant NRG-1 in all these models. We will also evaluate signs of toxicity in these models without performing a full scale toxicology experiment at this stage. In conclusion, there is robust evidence from our and other laboratories that recombinant NRG-1 has protective effects in various chronic diseases, but the route of administration is prohibitive for wider applicability in the clinic. If this project is successful in identifying a small molecule agonist of ErbB4, we might have the key to novel cures for various chronic diseases.

Researcher(s)

• Promoter: Segers Vincent
• Co-promoter: De Keulenaer Gilles

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

The majority of adults aged 65 years or older have elevated blood pressure (BP). This dramatically increases cardiovascular (CV) risk (i.e. increased risk for heart, brain or kidney problems). There is a large amount of BP-lowering drugs available. Unfortunately, they rarely succeed to reduce longterm CV risk completely, indicating that there is more to it than lowering BP alone. Indeed, stiffening of the large arteries (e.g. the aorta) also increases CV risk. Arterial stiffening has long been considered a structural adaptation of the arteries to elevated BP. However, recent studies report the opposite, i.e. that arterial stiffness precedes the elevation of BP seen with aging. Moreover, it was found that patients with high BP who respond poorly to their treatment are those with a stiffer aorta. This indicates that treating arterial stiffening in addition to hypertension may result in a better outcome. This was also suggested in the most recent guidelines of the European Society of Cardiology. Little is known about the mechanisms that cause arterial stiffening with aging. Structural components are known to alter arterial stiffness. Although the details are unknown, active components of the arterial wall have been shown to play a role also. Here, we want to investigate how active components determine arterial stiffness. Understanding these mechanisms is crucial if we aim to improve health care management in patients with elevated arterial BP and arterial stiffness.

Researcher(s)

• Promoter: De Keulenaer Gilles
• Co-promoter: Fransen Paul
• Fellow: Leloup Arthur

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

A disturbed maternal metabolism like in obesity or type II diabetes has clearly been associated with disappointing fertility. We extensively showed that such metabolic disorders have direct effects on the micro-environment of the growing and maturing oocyte, ultimately leading to reduced oocyte and embryo quality. Obesity is a global health threatening problem and recent studies indicated that maternal obesity may result in significant health issues in the offspring. More in depth mechanistic research clearly pointed out the importance of uterine programming in early pregnancy. It is not known however whether the metabolic status of obesity as such and/or potential direct effects of the typical fat rich western type diet are responsible for these observations. Based on the epidemiological relevance of obesity and hypercholesterolemia we hypothesize that obesity or an obesogenic diet of the mother around conception or during the entire pregnancy will alter the micro-environment of the growing embryo and fetus. This will change uterine programming ultimately leading to compromised offspring's health and reproductive physiology. To systematically investigate this hypothesis, we will feed female LDLR knock-out mice (LDLR-/-) an obesogenic diet A) several weeks before conception resulting in maternal obesity at conception or B) solely around conception or C) throughout the entire pregnancy. The offspring will be cross-fostered upon birth and will be used to study the general health of the offspring, the ovarian follicular reserve and the process of folliculo- and oogenesis, the offspring's pre-implantation embryo physiology and gene expression pattern and the receptivity of the offspring's uterus to support full pregnancy resulting in healthy offspring. By using this strategic experimental model we will be able to find the most sensitive window during pregnancy for uterine programming of reproduction, and it allows us to study the effects on every specific step on reproductive functioning. We believe that this project proposal may significantly contribute to the concept of "Developmental Origin of Health and Fertility" by further spreading the knowledge that epigenetic effects of maternal metabolism and diet may jeopardize health but also fertility in the offspring.

Researcher(s)

• Promoter: Leroy Jo
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Van Hoeck Veerle
• Fellow: Smits Anouk

Research team(s)

• Veterinary physiology and biochemistry

Project type(s)

• Research Project

Abstract

Tissue fibrosis is a pathological scarring process disrupting normal structure and function of many organs. Recent studies reported that neuregulin-1 (NRG-1), a growth factor with cardioprotective and -regenerative properties, might play a role in fibrogenesis in heart failure and glomerulosclerosis. However, it is currently undetermined whether NRG-1 plays a general role in tissue fibrosis. We recently filed a patent claiming the use of NRG-1 to treat fibrotic disorders. In this project, we focus on preclinical studies on the effects of NRG-1 on lung-fibrosis. We will study moratility and compare the effects to Nintedanib or perfinidone.

Researcher(s)

• Promoter: Segers Vincent
• Co-promoter: De Keulenaer Gilles

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

The majority of adults aged 65 years or older have elevated blood pressure (BP). This dramatically increases cardiovascular (CV) risk (i.e. increased risk for heart, brain or kidney problems). There is a large amount of BP-lowering drugs available. Unfortunately, they rarely succeed to reduce longterm CV risk completely, indicating that there is more to it than lowering BP alone. Indeed, stiffening of the large arteries (e.g. the aorta) also increases CV risk. Arterial stiffening has long been considered a structural adaptation of the arteries to elevated BP. However, recent studies report the opposite, i.e. that arterial stiffness precedes the elevation of BP seen with aging. Moreover, it was found that patients with high BP who respond poorly to their treatment are those with a stiffer aorta. This indicates that treating arterial stiffening in addition to hypertension may result in a better outcome. This was also suggested in the most recent guidelines of the European Society of Cardiology. Little is known about the mechanisms that cause arterial stiffening with aging. Structural components are known to alter arterial stiffness. Although the details are unknown, active components of the arterial wall have been shown to play a role also. Here, we want to investigate how active components determine arterial stiffness. Understanding these mechanisms is crucial if we aim to improve health care management in patients with elevated arterial BP and arterial stiffness.

Researcher(s)

• Promoter: De Keulenaer Gilles
• Co-promoter: Fransen Paul
• Fellow: Leloup Arthur

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Kidney failure is a frequent cause of increased morbidity and mortality. To date, no conclusive pharmacological therapies for kidney failure exist and does it frequently lead to kidney dialysis or transplantation. We recently filed a patent claiming the preventive effects of this specific protein against the development of type 1 diabetic nephropathy. We want to expand this claim to other forms of acute or chronic kidney disease.

Researcher(s)

• Promoter: Segers Vincent
• Co-promoter: De Keulenaer Gilles

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Little is known about the mechanisms that cause arterial stiffening with aging. Structural components are known to alter arterial stiffness. Although the details are unknown, active components of the arterial wall have been shown to play a role also. Here, we want to investigate whether and how active components determine arterial stiffness. Understanding these mechanisms is crucial if we aim to improve health care management in patients with elevated arterial BP and arterial stiffness.

Researcher(s)

• Promoter: De Keulenaer Gilles
• Co-promoter: Fransen Paul
• Fellow: Leloup Arthur

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the Hercules Foundation. UA provides the Hercules Foundation research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: De Meyer Guido
• Co-promoter: Claeys Marc
• Co-promoter: De Keulenaer Gilles
• Co-promoter: D'Haese Patrick
• Co-promoter: Loeys Bart
• Co-promoter: Vrints Christiaan

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Our goal is to examine the effect of the neuregulin-1 (NRG-1) on left ventricular (LV) diastolic (dys)function. LV diastolic dysfunction is the predominant abnormality of LV performance in about 50% of patients with chronic heart failure. It impairs LV filling and exercise tolerance, and is associated with increased morbidity and mortality.

Researcher(s)

• Promoter: De Keulenaer Gilles

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Rupture of atherosclerotic plaques remains the main cause of acute cardiovascular syndromes and death. The need for novel plaque stabilizing therapies is high, but adequate animal models of plaque rupture are lacking. We recently discovered that apolipoprotein E knock-out (ApoE-/-) mice with a heterozygous mutation (C1039G+/-) in the fibrillin-1 (Fbn1) gene show elastin fragmentation and arterial stiffness which leads to acute plaque rupture, myocardial infarction, stroke and sudden death. Although elastin fragmentation seems to trigger plaque rupture in ApoE-/- Fbn1C1039G+/- mice, there is currently insufficient evidence that supports this hypothesis. Therefore, the present research proposal aims to use ApoE-/-Abcc6-/- mice representing another mouse model of elastin degradation, yet via an alternative mechanism that involves progressive mineralization of the vessel wall. After confirmation of elastin fragmentation in ApoE-/-Abcc6-/- mice, the key objectives of the project are: 1) Characterization of ApoE-/-Abcc6-/- mice for atherosclerotic plaque development and rupture. 2) Validation of this mouse model for plaque rupture with established plaque stabilizing drugs (statins). 3) Study of the effects of everolimus as a novel potential plaque stabilizing therapy. Overall, this research proposal could provide better insights in the mechanisms of plaque rupture, and would allow quick evaluation of potential plaque stabilizing therapies on genuine clinical end points of plaque rupture in mice.

Researcher(s)

• Promoter: Martinet Wim
• Co-promoter: De Keulenaer Gilles
• Fellow: Van der Veken Bieke

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

The "phenotype" of patients with chronic heart failure is gradually changing from a dilated, poorly contracting left ventricle (LV) to a non-dilated, "thickened" ventricle (called "concentric" hypertrophy) with a normal global pump function (referred to as "heart failure with a preserved ejection fraction" or "HFPEF"). The reason for this phenotypic shift is unclear but relates to aging of the population and the increasing incidence of obesity, hypertension and type II diabetes, especially in postmenopausal women. How these risk factors, mostly in combination, promote HFPEF is unknown. Clinically, HFPEF is a diagnostic challenge and requires the development of novel therapeutic strategies, as traditional heart failure treatments have no proven benefit in HFPEF. In this project we will develop a new animal model of HFPEF by step-wise introducing risk factors (diabetes, hypertension, post-menopausal female gender and aging). The pathophysiology of HFPEF is incompletely understood but impaired LV filling due to slow LV relaxation and reduced LV compliance (altogether described as "diastolic dysfunction") seems to be a predominant mechanism. We predict that abovementioned risk factors accelerate the development of diastolic dysfunction and HFPEF. Next, we hypothesize that the risk factors for HFPEF direct the heart versus this HFPEF phenotype by affecting the balance between adaptive and disease-inducing signaling pathways in the heart. Changing this balance may prevent LV dilatation and pump failure but at the cost of developing concentric hypertrophy with impaired LV diastolic function. We will analyze the behavior of two important cardioprotective pathways, namely insulin like growth factor-1 (IGF1) and neuregulin-1(NRG1)/ErbB during the development of HFPEF induced by its specific risk factors. The cardioprotective nature of these pathways has been established under several cardiovascular diseases but their behavior and role in the development of HFPEF is completely unknown. IGF1 and NRG1 both rely on tyrosine kinase receptors and subsequent Akt activation to promote growth and stress-resistance of cardiac cells. This way they can protect the heart against LV dilation and pump failure, but may contain the risk of promoting concentric hypertrophy and HFPEF instead. On the other hand, however, IGF1 or NRG1 may ameliorate LV compliance and diastolic function by affecting the sarcomeric protein titin and by activation of the endothelial nitric oxide synthase, both powerful determinants of LV compliance. To unravel this apparent paradox, we will inhibit and activate these pathways using recombinant proteins and specific tyrosine kinase inhibitors respectively to examine whether the HFPEF phenotype is accentuated or soothed. Over the past decade IGF1 and NRG1 came forward as powerful cardioprotective agents failure in conditions of myocardial ischemia and phase I clinical trials have been initiated. Therefore uncovering the effects of IGF1 and NRG1 on diastolic function and the development of HFPEF is clinically very important. In summary, the presented research project will shed light on the correlation between specific risk factors such as hypertension, type II diabetes, aging and postmenopausal female gender and the HFPEF phenotype. Next, this project is the first to investigate the effects IGF1 and NRG1/ErbB pathways on diastolic function and the development of HFPEF.

Researcher(s)

• Promoter: De Keulenaer Gilles
• Promoter: Lemmens Katrien
• Co-promoter: De Keulenaer Gilles

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

The MEDIA consortium investigates:1) how metabolic derangements contribute to diagnostic heart failure (DHF); 2) how diagnostic algorithms for DHF can be improved by assessing metabolic risk; 3) how correction of metabolic risk can open new therapeutic perspectives for DHF.

Researcher(s)

• Promoter: De Keulenaer Gilles

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

In the present research project we will examine the function of the neuregulin-ErbB system during and following acute myocardial damage, induced by ischemia/reperfusion (I/R). We anticipate that ErbB signaling will be induced by paracrine neuregulin and possibly other cardio-active factors based on the observation that other stress factors (hemodynamic, oxidative and cardiotoxic stress) activate the ErbB system. I/R injury induces ventricular remodelling, fibrosis and diastolic dysfunction. Our hypothesis is that activation of the ErbB system influences I/R-induced processes in an adaptive manner.

Researcher(s)

• Promoter: De Keulenaer Gilles
• Fellow: Hervent Anne-Sophie

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims to better understand the effects of chronic dipeptidyl peptidase (DPP) inhibition on pre-defined aspects of cardiovascular, renal and bone (patho)physiology. Inhibitors with defined selectivity profiles will be developed as tools. Expression and inhibition of DPP4 and related peptidases will be studied on the molecular level, in cultured cells and in rat models of ischemia/reperfusion injury of heart and kidney.

Researcher(s)

• Promoter: De Meester Ingrid
• Co-promoter: Augustyns Koen
• Co-promoter: De Keulenaer Gilles
• Co-promoter: D'Haese Patrick
• Co-promoter: Lambeir Anne-Marie

Research team(s)

• Medical Biochemistry

Project type(s)

• Research Project

Abstract

Aims: 1. to mimic trastuzumab-induced cardiotoxicity in rat in order to clarify underlying mechanisms. 2. to explain underlying mechanisms of NRG-1 mediated cardioprotection and "reverse remodelling", focusing on the role of NO en PDE5. 3. to investigate interaction between the NRG-ErbB system and the renin-angiotensin-aldosteron system.

Researcher(s)

• Promoter: De Keulenaer Gilles
• Fellow: Lemmens Katrien

Research team(s)

Project type(s)

• Research Project

Abstract

In this project, we will study in which (patho)physiological conditions in vivo the cardiac NRG-ErbB system becomes activated and to what extent cardiac function then becomes dependent on this. Four clinically relevant conditions will be tested (arterial hypertension, left ventricular volume overload, intense physical exercise, diabetes). The activity of the cardiac NRG-ErbB system will be determined at the molecular level (ligand and receptor). -Cardiac functionality dependency will be verified by inhibition studies (intra-venous administration of inhibiting antibodies against ErbB2), with subsequent analyses of function, molecular features and histology of the myocardium.

Researcher(s)

• Promoter: De Keulenaer Gilles

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

The central hypothesis of this project is that disturbances of endothelium-cardiomyocyte cross-talk contribute to the patrhogenesis of diabetes-induced cardiomyopathy. The aims are: 1. To test whether treatment with an endothelium-protective farmacon NEBIVOLOL protects against development of diabetic CMP (and against vascular endothelial dysfunction) 2. To test whether a disturbed paracrine endothelial regulation of cardiac function through neuregulin-1 contributes to diabetic CMP.

Researcher(s)

• Promoter: De Keulenaer Gilles
• Fellow: Doggen Kris

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: De Keulenaer Gilles
• Promoter: De Meyer Guido

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

The central hypothesis of this project is that disturbances of endothelium-cardiomyocyte cross-talk contribute to the patrhogenesis of diabetes-induced cardiomyopathy. The aims are: 1. To test whether treatment with an endothelium-protective farmacon NEBIVOLOL protects against development of diabetic CMP (and against vascular endothelial dysfunction) 2. To test whether a disturbed paracrine endothelial regulation of cardiac function through neuregulin-1 contributes to diabetic CMP.

Researcher(s)

• Promoter: De Keulenaer Gilles
• Fellow: Doggen Kris

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: De Keulenaer Gilles
• Fellow: Segers Vincent

Research team(s)

Project type(s)

• Research Project

Abstract

Cardiac endothelium (in myocardial capillaries and endocardium) is an essential structural component of the heart; by virtue of its anatomy at the interface between bIood and myocardium, the cardiac endothelium senses the circulating environment and Interacts with subjacent cardlomyocytes. In 1986, our laboratory showed that these interactions have modulatory effects on the mechanical performance of the heart. To date, there is strong scientific evidence for a role of cardiac endothelium in development and growth, rythmicity and mechanical performance of the heart. Furthermore, there emerging evidence that in pathophysiological conditions, like during endothelial activation, cardiac endothelium participates in intrinsic and extrinsic responses of the heart to compensate for ventricular pump dysfunction, and that cardiac endothelial dysfunction leads to irreversible heart failure. The first work hypothesis of this grant proposal is that cardiac endothelium, as a physiological modulator of myocardial function, displays unique cellular and molecular properties. These properties and their importance for cardiac function are just beginning to be elucidated (e.g. synthesis and secretion of neuregulin), but are still only partially understood. The second work hypothesis is that cardiac endothelium plays a role in cardiac regeneration, especially by influencing stem cell traffic (adhesion and trans-endothelial migration). Interactions between cardiac endothelium and stem cells have already been observed in our laboratory, but the mechanims are still unclear.

Researcher(s)

• Promoter: De Keulenaer Gilles

Research team(s)

Project type(s)

• Research Project

Abstract

Diabetes mellitus is often accompanied by important cardiovascular abnormalities. These include degenerative vascular diseases (micro- and macroangiopathy) and "diabetic cardiomyopathy", a cause of diastolic heart failure with an important contribution to morbidity and mortality. Currently, there is no specific treatment for diabetic cardiomyopathy. In addition, there is a poor understanding of the (sub)cellular processes underlying this disease. Endothelial dysfunction is an important defect in diabetes, but its correlation with diabetic cardiomyopathy is unclear. This study will attempt to characterize the changes in active relaxation and passive stiffness, both parameters of diastolic function, in the heart of the diabetic rat. The same animal model will be used to study the following questions: does dysfunction of the cardiac endothelium (in the microvasculature and the endocardium) contribute to the initiation and progression of the functional and structural changes that typify the heart of the diabetic rat, and, if so, is early pharmacological protection of the endothelium with ACE inhibitors, statins, thiazolidinediones or antioxidants capable of slowing down or preventing the development of diabetic cardiomyopathy?

Researcher(s)

• Promoter: De Keulenaer Gilles
• Fellow: Doggen Kris

Research team(s)

Project type(s)

• Research Project

Abstract

Cardiac endothelium, an essential anatomical and functional component of the heart, will be studied with respect to two fundamental questions: (i) how does cardiac endothelium interact with mobilized adult stem cells (ii) what is the molecular basis underlying the unique physiological features of cardiac endothelium?

Researcher(s)

• Promoter: De Keulenaer Gilles

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: De Keulenaer Gilles
• Fellow: Lemmens Katrien

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: De Keulenaer Gilles
• Fellow: Segers Vincent

Research team(s)

Project type(s)

• Research Project

Abstract

Increased biomechanical strain on the ventricular wall is a common characteristic of acquired and inherited forms of left ventricular dysfunction and one of the most important triggers of disease progression and cardiac failure. The significance of biomechanical strain in the pathogenesis of heart failure is reinforced by recent evidence that molecular events responsible for myocardial hypertrophy and remodeling are controlled by biomechanical strain. In the present proposal, we outline laboratory and prospective clinical studies to find a link between mechanically controlled processes in cardiac myocytes on the one hand, and prognosis of heart failure and disease progression on the other hand.

Researcher(s)

• Promoter: De Keulenaer Gilles

Research team(s)

Project type(s)

• Research Project

Abstract

The goal of this study is to describe autophagic cell death during the progression of heart failure. Therefore, we plan the implementation of a chronic mouse model of cardiac pressure overload. To realize these plans, we have trained personnel and side-technology, but need additional micro- surgical technology.

Researcher(s)

• Promoter: De Keulenaer Gilles
• Co-promoter: Demolder Marc

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: De Keulenaer Gilles
• Promoter: Hendrickx Jan
• Co-promoter: Fransen Paul

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: De Keulenaer Gilles

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: De Keulenaer Gilles

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: De Keulenaer Gilles

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Brutsaert Dirk
• Promoter: De Keulenaer Gilles
• Fellow: Hendrickx Jan

Research team(s)

Project type(s)

• Research Project

Abstract

Haem-oxygenase (HO) kreeg recent een belangrijke rol toegewezen in de controle en protectie van het cardiovasculaire systeem. In het hart komen twee vormen van HO voor: het constitutieve HO-2 en de induceerbare vorm HO-1, ook gekend als `heat shock protein'-32. Wij wensen de hypothesen te testen dat 1) HO-1 en HO-2 de communicatie tussen cardiaal endotheel en hartspiercellen beïnvloeden en dat 2) HO-1 cytoprotectieve eigenschappen vertoont in het bijzonder tegen oxidatieve stress.

Researcher(s)

• Promoter: Sys Stanislas
• Co-promoter: Brutsaert Dirk
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Fransen Paul

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims at studying molecular and cellular events involved in tissue remodeling after injury. The following issues will be addressed : the activation of endothelial cells, recruitment of leukocytes and platelets, the effects of infiltrating and residents on the turn-over of the extracellular matrix and the pharmacological modulation of these processes.

Researcher(s)

• Promoter: Herman Arnold
• Co-promoter: Brutsaert Dirk
• Co-promoter: De Broe Marc
• Co-promoter: De Keulenaer Gilles

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project