Research Lynn Roth

Abstract

Age-related diseases such as cardiovascular (CV) disease have a substantial impact on our quality of life. The aging vasculature is characterized by arterial stiffness, which is an independent predictor of CV complications. There is accumulating evidence that loss of autophagy, a cellular housekeeping mechanism, facilitates vascular aging. Recent literature describes that endotrophin (ETP) serum levels (a cleavage product of COL6A3) are associated with arterial stiffness and CV events. Furthermore, we have observed that autophagy deficiency in vascular smooth muscle cells (VSMCs) results in a higher expression of ETP. However, an in-depth analysis of the link between ETP and autophagy and how this affects vascular aging is lacking. Therefore, we aim to investigate if ETP accelerates vascular aging and whether it contributes to the detrimental effects of autophagy deficiency in VSMCs. This will answer three research questions: (1) What are the biological effects of ETP on vascular cell function, and do they explain some of the detrimental effects of VSMC autophagy deficiency? (2) Can ETP contribute to accelerated vascular aging in mice? (3) Does defective VSMC autophagy exert its main effects on the vascular wall through enhanced expression of ETP? Overall, this project will bring us one step closer in understanding how an age-related decline in autophagy can lead to CV disease and might result in identifying ETP as a novel therapeutic target.

Researcher(s)

• Promoter: Roth Lynn
• Fellow: Jacobs Charlotte

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Elastin is responsible for the elasticity of the vessel wall, but due to repetitive stretches and relaxations as we age, it will fracture, leading to arterial stiffness and the release of soluble elastin-derived peptides (EDPs). Some of these EDPs are biologically active by interacting with the elastin receptor complex (ERC) and can play a role in the development of cardiovascular disease (CVD). Existing literature points towards a decline in autophagy by EDPs. Autophagy is a protective mechanism, that recycles damaged cell products into building blocks that are used to maintain cellular health. Lower autophagy levels can contribute to CVD. If EDPs can reduce autophagy, this might be an important mechanism by which they exert their detrimental effects. Therefore, we would like to investigate whether EDPs can reduce autophagy and how this affects arterial stiffness and CVD. This will answer three research questions: (1) Can EDPs affect cellular function and lead to autophagy deficiency in vascular cells? (2) What is the role of ERC signalling in the progression of arterial stiffness and is autophagy deficiency responsible for the observed effects? (3) Can ERC signalling enhance atherogenesis and is autophagy deficiency responsible for the observed effects? Overall, this research plan aims to better understand the role of EDPs in autophagy decline, vascular ageing and arterial stiffness in order to prevent or slow down this process and to improve quality of life.

Researcher(s)

• Promoter: Roth Lynn

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Elastin is responsible for the elasticity of the vessel wall, but due to repetitive stretches and relaxations as we age, it will fracture, leading to arterial stiffness and the release of soluble elastin-derived peptides (EDPs). Some of these EDPs are biologically active and can play a role in the development of cardiovascular disease (CVD). Existing literature points towards a decline in autophagy by EDPs. Autophagy is a protective mechanism, that recycles damaged cell products into building blocks that are used to maintain cellular health. Lower autophagy levels can contribute to vascular disease. If EDPs can reduce autophagy, this might be an important mechanism by which they exert their detrimental effects. However, this has never been proven. Therefore, we would like to investigate whether EDPs can reduce autophagy and how this affects arterial stiffness. This will answer three research questions: (1) Can EDP signalling affect cellular function and lead to autophagy deficiency in vascular cells? (2) What is the role of EDPs in the progression of arterial stiffness and (3) is autophagy deficiency responsible for the observed effects? Overall, this research plan aims to better understand the role of EDPs in autophagy decline, vascular ageing and arterial stiffness in order to prevent or slow down this process and to improve quality of life.

Researcher(s)

• Promoter: Roth Lynn
• Co-promoter: Martinet Wim
• Fellow: Van Praet Melissa

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

In the last century, the enormous improvements in life expectancy have led to a global population that has grown considerably older. The number of people over 65 is expected to increase from an estimated 524 million in 2010 to nearly 1.5 billion in 2050 (source WHO). Therefore, age-related diseases such as cardiovascular disease (CVD), diabetes, kidney disease and neurological disorders have a significant impact on our quality of life and represent a huge social and economic burden. Vascular ageing is characterized by structural and functional changes in the wall of large arteries, leading to arterial stiffness, which is an independent predictor of cardiovascular complications. Moreover, there is increasing evidence that it is a key driving force for multiple age-related cardiac, renal and cerebral pathologies. This challenge aims to better understand the pathophysiological mechanisms causing vascular ageing and arterial stiffness in order to prevent or delay this process and improve quality of life. The focus will be on the role of autophagy in vascular ageing, which is a homeostatic process that supports cell survival under stressful conditions. The autophagic process becomes impaired as we age, contributing to the development of age-related diseases. However, many questions about why autophagy declines and how it can be therapeutically targeted, still remain unanswered.

Researcher(s)

• Promoter: Roth Lynn
• Co-promoter: De Meyer Guido
• Co-promoter: Guns Pieter-Jan
• Co-promoter: Martinet Wim

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

The number of people over 65 years of age is projected to grow from an estimated 524 million in 2010 to nearly 1.5 billion in 2050, which means that age-related diseases will have a substantial impact on our quality of life. As we get older, changes occur in the wall of our large arteries, making them more stiff. This phenomenon is called arterial stiffness and it is an important driving force of cardiovascular disease (CVD) and other age-related diseases. If we can understand the mechanisms that lead to arterial stiffness, we can use that information to develop novel treatment strategies. In the present research proposal, the role of elastin-derived peptides (EDPs) and autophagy in the occurrence of arterial stiffness and CVD, will be investigated. Elastin is responsible for the elasticity of the vessel wall, but due to repetitive stretches and relaxations, it will fracture, leading to arterial stiffness and the release of soluble EDPs. Some of these EDPs are biologically active and can play a role in the development of CVD. Existing literature points towards a decline in autophagy by EDPs. Autophagy is a protective mechanism, that recycles damaged cell products into building blocks that can be used to maintain cellular health, especially in stressful conditions. Lower autophagy levels can contribute to CVD. If EDPs can reduce autophagy, this might be an important mechanism by which they exert their detrimental effects. However, this has never been proven. Therefore, we would like to investigate whether EDPs can reduce autophagy and how this affects arterial stiffness and CVD. This will answer two important research questions 1) What is the role of EDPs in the progression of arterial stiffness and CVD? and 2) Can EDPs lead to lower autophagy levels and to what extent does this contribute to the physiological effects of EDPs? A third question that we would like to answer is: Which molecular mechanisms drive the effects of lower autophagy levels on ageing and CVD? This can help to determine interesting therapeutic targets. The focus will be on vascular smooth muscle cells (VSMCs), which is an important cell type in the vessel wall and the development of arterial stiffness. The absence of autophagy in VSMCs leads to changes in cell function that can enhance CVD. We have identified a link between the lack of autophagy in VSMCs and endotrophin, which is a type VI collagen cleavage product. It has been described that higher serum endotrophin levels are predictive of cardiovascular events and associated with arterial stiffness, which makes it an interesting target. Therefore, we will determine the endotrophin levels produced by VSMCs that lack autophagy and define its role in the functional changes that occur in these cells. The final question we will investigate is: Can we identify compounds that target EDP signalling and/or autophagy in order to prevent or treat arterial stiffness and CVD? At the moment the main focus will be on targeting autophagy by olive polyphenols. These natural dietary products display health-promoting properties, which can be related to higher autophagy levels. Therefore, we will evaluate the effects of polyphenols on vascular function, arterial stiffness and CVD progression, including the role of autophagy, which might identify them as interesting options to treat age-related diseases. Overall, this research plan aims to better understand the mechanisms that drive vascular ageing and arterial stiffness in order to prevent or slow down this process and to improve quality of life.

Researcher(s)

• Promoter: Roth Lynn
• Fellow: Roth Lynn

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Elastin is responsible for the elasticity of the vessel wall, but due to repetitive stretches and relaxations as we age, it will fracture, leading to arterial stiffness and the release of soluble elastin-derived peptides (EDPs). Some of these EDPs are biologically active and can play a role in the development of cardiovascular disease (CVD). Existing literature points towards a decline in autophagy by EDPs. Autophagy is a protective mechanism, that recycles damaged cell products into building blocks that are used to maintain cellular health. Lower autophagy levels can contribute to CVD. If EDPs can reduce autophagy, this might be an important mechanism by which they exert their detrimental effects. However, this has never been proven. Therefore, we would like to investigate whether EDPs can reduce autophagy and how this affects arterial stiffness and CVD. This will answer three research questions: (1) Can EDP signalling affect cellular function and lead to autophagy deficiency in vascular cells and monocytes? (2) What is the role of EDPs in the progression of arterial stiffness and is autophagy deficiency responsible for the observed effects? (3) Can EDP signalling enhance atherogenesis and is autophagy deficiency responsible for the observed effects? Overall, this research plan aims to better understand the role of EDPs in autophagy decline, vascular ageing and arterial stiffness in order to prevent or slow down this process and to improve quality of life.

Researcher(s)

• Promoter: Roth Lynn
• Fellow: Van Praet Melissa

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Arterial stiffness, a major health issue, progresses with age. Dietary polyphenols improve vascular stiffening via vascular, inflammatory and other mechanisms, most likely due to their metabolites. Although promising effects for prevention and treatment of arterial stiffness have been reported for blueberry and olive polyphenols, it is largely unknown which polyphenol metabolites interact with which underlying mechanisms. In this project, polyphenol metabolites will be generated in gastrointestinal and liver simulations and will be identified subsequently. Since gut microbial composition is linked to arterial stiffness, is affected by polyphenols and is different in the elderly, an aged and young biotransformation model will be compared. Metabolites will be tested, separately and in mixtures analogous to the in vivo situation, in assays on vascular, oxidative, inflammatory and other mechanisms contributing to arterial stiffness. Also, polyphenol effects on gut microbial composition will be evaluated. This combination of analyses renders this project innovative and original. Results will provide a unique insight on polyphenol metabolism and the influence of age thereupon, and on polyphenol prebiotic-like effects. Moreover, they will increase understanding regarding the influence of olive and blueberry polyphenol metabolites on fundamental processes underlying arterial stiffness and multiple other pathological conditions, facilitating future research.

Researcher(s)

• Promoter: Hermans Nina
• Co-promoter: Roth Lynn
• Co-promoter: Tuenter Emmy
• Fellow: Lauwers Stef

Research team(s)

• Natural Products & Food Research and Analysis - Pharmaceutical Technology (NatuRAPT)

Project type(s)

• Research Project

Abstract

In order to be able to exert biological activity, phytochemicals which are administered orally need to be absorbed from the gut and reach the general circulation. In our lab, simulations with a gastrointestinal dialysis model with colon phase (GIDM-colon) are already performed to assess gastrointestinal biotransformation and passive absorption. However, active absorption and efflux mechanisms, causing flow of metabolites from the enterocytes towards the gut lumen, are not taken into account. With the current Small Research Grant we intend to expand our GIDM-colon set-up with the MIVO® device (Multi In Vitro Organ device). This device can be seeded with human intestinal tissue and thus can mimic the intestinal barrier to replicate human intestinal absorption. Since it is a continuous double flow system, it is devoid of some of the drawbacks of classical Caco-2 cell experiments. Chlorogenic acid and rutin, two phenolic phytochemicals that are widely present in food, are selected as model compounds to assess the performance of this new device. Experiments will be performed with these two compounds as such and after addition to faeces samples. Results will be compared to previously obtained results of our GIDM-colon system and to in vitro and in vivo literature data.

Researcher(s)

• Promoter: Roth Lynn
• Promoter: Tuenter Emmy

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Atherosclerotic plaque rupture is responsible for 3.9 million deaths in Europe every year. Thus, further research to determine the underlying molecular mechanisms of this disease is greatly needed in order to define novel treatment strategies. It is known that impaired autophagy, a cellular housekeeping mechanism, has a major impact on the progression and destabilization of atherosclerotic plaques. Therefore, inducing autophagy seems a good therapeutic strategy and we want to specifically target cellular pathways downstream of autophagy. This allows us to modulate the detrimental effects generated by autophagy deficiency, without affecting autophagy itself. In a recent study we observed a strong upregulation of Col6a3 in autophagy deficient vascular smooth muscle cells (VSMCs), which is known to lead to increased levels of endotrophin, a cleavage product of COL6A3. Higher serum endotrophin levels in patients are predictive of cardiovascular events and associated with arterial stiffness, which makes this protein an interesting therapeutic target. Therefore, we aim to identify endotrophin as the key player in the harmful effects of autophagy deficiency on normal VSMC function. In order to reach this objective, we will determine the endotrophin levels produced as a result of autophagy deficiency in VSMCs and define its role in the functional changes (proliferation, migration, collagen production, senescence) that occur in these cells. This is important in understanding how a decline in autophagy can lead to cardiovascular disease. Furthermore, it might result in identifying endotrophin as a novel therapeutic target.

Researcher(s)

• Promoter: Roth Lynn

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Atherosclerotic plaque rupture is the leading cause of acute cardiovascular syndromes and is responsible for 3.9 million deaths in Europe every year. Preventive strategies are greatly needed to reduce the health care burden of cardiovascular disease (CVD). The Mediterranean diet results in a lower CVD risk, with virgin olive oil as an important element. Many of the health-promoting effects are ascribed to the olive polyphenols (OPs), which have shown to reduce oxidative stress and were recently linked with autophagy. Autophagy is a cellular housekeeping mechanism and autophagy deficiency is detrimental in the development of CVD. Thus, inducing autophagy is likely to be an effective preventive strategy. OPs were identified as natural autophagy inducers, but further research is needed to define the contribution of this mechanism to their antioxidant and atheroprotective effects. Therefore, we will determine the most potent autophagy-inducing OP in endothelial cells and vascular smooth muscle cells and define the underlying molecular mechanisms linked to autophagy. The most potent OP will be selected for further in vivo analysis, in which we will identify its effects on the functionality of healthy blood vessels, CVD prevention and oxidative stress. This project will give insight in the mechanism of action of OPs and is an important step towards the implementation of OP-based nutraceuticals for the prevention of CVD.

Researcher(s)

• Promoter: Hermans Nina
• Co-promoter: Roth Lynn
• Fellow: Steenput Bieke

Research team(s)

Project type(s)

• Research Project

Abstract

Atherosclerotic plaque rupture is the leading cause of acute cardiovascular syndromes and is responsible for 3.9 million deaths in Europe every year. Preventive strategies are greatly needed to reduce the health care burden of cardiovascular disease (CVD). The Mediterranean diet results in a lower CVD risk, with virgin olive oil as its key element. Many of the health-promoting effects are ascribed to the olive polyphenols (OPs), which are known to be antioxidants, but recently a link with autophagy induction was shown. Autophagy is a cellular housekeeping mechanism and autophagy deficiency is detrimental in the development of CVD. Thus, inducing autophagy is likely to be an effective preventive strategy. OPs were identified as natural autophagy inducers, but further research is needed to define the contribution of this mechanism to their atheroprotective effects. Therefore, we aim to elucidate the role of endothelial cell autophagy in the atheroprotective properties of OPs. The research objectives are divided in 2 work packages: (1) Selection of the most potent autophagy-inducing OP and the most therapeutically effective dose, (2) Investigation of the atheroprotective effects of an OP and the role of endothelial cell autophagy. This project will give insight in the mechanism of action of OPs and is an important step towards the implementation of OP nutraceuticals for the prevention of cardiovascular disease.

Researcher(s)

• Promoter: Roth Lynn

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Atherosclerotic plaque rupture is the leading cause of acute cardiovascular syndromes and is responsible for 3.9 million deaths in Europe every year. Preventive strategies are greatly needed to reduce the health care burden of cardiovascular disease (CVD). It is well-known that the Mediterranean diet results in a lower CVD risk, with virgin olive oil as an important element. Many of the health-promoting effects are ascribed to the olive polyphenols. Over the years, studies have shown that olive polyphenols reduce oxidative stress and inflammation and enhance vascular function. In recent literature, these effects were related to the upregulation of autophagy. Autophagy is a cellular housekeeping mechanism and autophagy deficiency is detrimental in the development of CVD. Thus, inducing autophagy is likely to be an effective preventive strategy. Olive polyphenols were identified as natural autophagy inducers, but further research is needed to define the contribution of this mechanism to their antioxidant and atheroprotective effects. Therefore, we will determine the most potent autophagy-inducing olive polyphenol in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) and define the underlying molecular mechanisms linked to autophagy. The most potent polyphenol will be selected for further in vivo analysis, in which we will identify its effects on the functionality of healthy blood vessels, CVD prevention and oxidative stress, with a special focus on the role of EC and VSMC autophagy. This project will give insight in the mechanism of action of olive polyphenols and is an important step towards the implementation of olive polyphenol-based nutraceuticals for the prevention of CVD.

Researcher(s)

• Promoter: Hermans Nina
• Co-promoter: Roth Lynn
• Fellow: Steenput Bieke

Research team(s)

Project type(s)

• Research Project

Abstract

Atherosclerotic plaque rupture is the leading cause of acute cardiovascular syndromes and is responsible for 3.9 million deaths in Europe every year. Preventive strategies are greatly needed to reduce the health care burden of cardiovascular disease (CVD). The Mediterranean diet results in a lower CVD risk, with virgin olive oil as its key element. Many of the health-promoting effects are ascribed to the olive polyphenols (OPs) and recently a link with autophagy induction was shown. Autophagy is a cellular housekeeping mechanism and autophagy deficiency is detrimental in the development of CVD. Thus, inducing autophagy is likely to be an effective preventive strategy. OPs were identified as natural autophagy inducers, but further research is needed to define the contribution of this mechanism to their atheroprotective effects. Therefore, we aim to elucidate the role of endothelial cell and vascular smooth muscle cell autophagy in the atheroprotective effects of OPs. The research objectives are divided in 3 work packages: (1) Selection of the most potent autophagy-inducing OP and the most therapeutically effective dose, (2) Investigation of the vasomotor effects of an OP and the role of autophagy and (3) Investigation of the atheroprotective effects of an OP and the role of autophagy. This project will give insight in the mechanism of action of OPs and is an important step towards the implementation of OP nutraceuticals for the prevention of cardiovascular disease.

Researcher(s)

• Promoter: De Meyer Guido
• Co-promoter: Martinet Wim
• Fellow: Roth Lynn

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Atherosclerotic plaque rupture remains the leading cause of acute cardiovascular syndromes and death. Therefore, additional therapy that reduces atherosclerosis or prevents plaque rupture is needed. Autophagy is a cellular housekeeping mechanism that under certain conditions induces cell death. Recent findings indicate that autophagy deficiency has a major impact on destabilization of advanced atherosclerotic plaques. In the current project we will focus on the role of autophagy in vascular smooth muscle cells (VSMCs), since these cells are key players in the development of atherosclerosis. Moreover, our research group discovered that defective autophagy in VSMCs leads to accelerated atherosclerosis. Thus, inducing autophagy seems a plausible therapeutic strategy to treat cardiovascular disease. However, none of the drugs that were specifically designed to modulate autophagy are currently approved for human use. These compounds often show low specificity for their molecular target and cell type, thereby activating autophagy at the whole-body level. Since autophagy induction can aggravate certain pathologies, such as cancer, these low-specific drugs impose health risks. Therefore, the current research project aims to overcome these risks and specificity problems by identifying the downstream molecular pathways and microRNAs involved in the harmful effects of autophagy deficiency in VSMCs. For this purpose, the mRNA and microRNA profile of autophagy deficient VSMCs will be analysed via next generation sequencing. As a result, we might reveal new drug targets with enhanced cell type specificity. Eventually, the current proposal can lead to novel anti-atherosclerotic therapies targeting the cellular pathways downstream of autophagy in VSMCs, which is more selective than directly modulating the autophagic process itself.

Researcher(s)

• Promoter: Roth Lynn

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 stabilising therapies is high, but adequate animal models are lacking. We recently discovered that ApoE-/- mice with a disturbed fibrillin production (ApoE-/-/C1039G+/- mice) fed a Western-type diet develop more unstable plaques as compared to ApoE-/- mice. Interestingly, acute plaque rupture and death occurred very frequently: 50% of the ApoE-/-/C1039G+/- mice died suddenly within 20 to 52 weeks, most likely due to cerebral embolism, whereas all ApoE-/- mice survived. Further optimisation and characterisation of this model could provide better insights in the mechanisms of plaque rupture, and also give for the first time the opportunity to evaluate potential plaque stabilising therapies on genuine clinical end points of plaque rupture (embolism, stroke and/or death) in mice. The aims of the project are: 1) Further optimisation and characterisation of the model. We will investigate whether additional destabilising stimuli can augment and speed up the incidence of plaque rupture, which is important for the evaluation of plaque stabilising therapies. 2) Validation of this model with established plaque stabilising drugs such as statins. 3) Study of the effects of novel potential plaque stabilising therapies (phytosterols, NO-donor).

Researcher(s)

• Promoter: De Meyer Guido
• Co-promoter: Martinet Wim
• Fellow: Roth Lynn

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 stabilising therapies is high, but adequate animal models are lacking. We recently discovered that ApoE-/- mice with a disturbed fibrillin production (ApoE-/-/C1039G+/- mice) fed a Western-type diet develop more unstable plaques as compared to ApoE-/- mice. Interestingly, acute plaque rupture and death occurred very frequently: 50% of the ApoE-/-/C1039G+/- mice died suddenly within 20 to 52 weeks, most likely due to cerebral embolism, whereas all ApoE-/- mice survived. Further optimisation and characterisation of this model could provide better insights in the mechanisms of plaque rupture, and also give for the first time the opportunity to evaluate potential plaque stabilising therapies on genuine clinical end points of plaque rupture (embolism, stroke and/or death) in mice. The aims of the project are: 1) Further optimisation and characterisation of the model. We will investigate whether additional destabilising stimuli can augment and speed up the incidence of plaque rupture, which is important for the evaluation of plaque stabilising therapies. 2) Validation of this model with established plaque stabilising drugs such as statins. 3) Study of the effects of novel potential plaque stabilising therapies (phytosterols, NO-donor).

Researcher(s)

• Promoter: De Meyer Guido
• Co-promoter: Martinet Wim
• Fellow: Roth Lynn

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project