Experimental Targets in Aneurysm Development

Title [sv]

Abstract [sv]

Bakgrund: Cardiovascular disease, including abdominal aortic aneurysm (AAA), is anenormous health care burden and ruptured AAA account for approximately 200,000 of annual deaths in the world. AAA is an inflammatory disease and despite long-term anti-inflammatory and lipid lowering treatment due to other underlying vascular disease the majority of AAA patients have, these drugs neither prevent nor inhibit aneurysm disease. Not a single drug treatment for aneurysm exist. This indicates that more specific immune cell targeting is required to inhibit aneurysm development. Our preliminary results indicate that anti-diabetic drugs could have an effect in the inhibition of aneurysm.Målsättning: To be able to find new therapeutic preventive strategies the molecular mechanisms behind the disease and drug targets needs to be elucidated in more detail. Based on previous studies we have identified several key factors that could be targeted by certain drugs. The main aim is to clarify pathophysiological and molecular mechanisms behind AAA disease and to find novel treatment strategies. The hypothesis is that certain drugs that focus on metabolic pathways has beneficial effects on the inhibition of aneurysm growth.Arbetsplan: Human samples, cell and animal models of aneurysm disease will be used to target novel pathways, immune cell activation and vascular remodelling via transcriptional regulation and by targeting glycolysis using the GLP-1 agonist semaglutide. Our previous results also show that Gpnmb and Clec7a, two glycoproteins, are inhibited by metformin, another anti-diabetic drug, as well as two other metabolic factors, irisin and ghrelin. The expression and role of these factors as biomarkers for disease and treatment will be studied in human patients. Betydelse: The importance of this research is to increase the knowledge of pathogenesis of AAA so that standardized surgery can be replaced by individual risk -adapted medication resulting in reduced mortality and fewer complications leading to better quality of life. Identification of drugs that can inhibit aneurysm would be of direct importance for the patients since there are currently no drugs available for this purpose. Also, reliable biomarkers used to follow disease progression and treatment would be beneficial. These markers could also be further studied for implication in the pathogenesis of aneurysm development.

Abstract [en]

Bakgrund: Cardiovascular disease, including abdominal aortic aneurysm (AAA), is anenormous health care burden and ruptured AAA account for approximately 200,000 of annual deaths in the world. AAA is an inflammatory disease and despite long-term anti-inflammatory and lipid lowering treatment due to other underlying vascular disease the majority of AAA patients have, these drugs neither prevent nor inhibit aneurysm disease. Not a single drug treatment for aneurysm exist. This indicates that more specific immune cell targeting is required to inhibit aneurysm development. Our preliminary results indicate that anti-diabetic drugs could have an effect in the inhibition of aneurysm.Målsättning: To be able to find new therapeutic preventive strategies the molecular mechanisms behind the disease and drug targets needs to be elucidated in more detail. Based on previous studies we have identified several key factors that could be targeted by certain drugs. The main aim is to clarify pathophysiological and molecular mechanisms behind AAA disease and to find novel treatment strategies. The hypothesis is that certain drugs that focus on metabolic pathways has beneficial effects on the inhibition of aneurysm growth.Arbetsplan: Human samples, cell and animal models of aneurysm disease will be used to target novel pathways, immune cell activation and vascular remodelling via transcriptional regulation and by targeting glycolysis using the GLP-1 agonist semaglutide. Our previous results also show that Gpnmb and Clec7a, two glycoproteins, are inhibited by metformin, another anti-diabetic drug, as well as two other metabolic factors, irisin and ghrelin. The expression and role of these factors as biomarkers for disease and treatment will be studied in human patients. Betydelse: The importance of this research is to increase the knowledge of pathogenesis of AAA so that standardized surgery can be replaced by individual risk -adapted medication resulting in reduced mortality and fewer complications leading to better quality of life. Identification of drugs that can inhibit aneurysm would be of direct importance for the patients since there are currently no drugs available for this purpose. Also, reliable biomarkers used to follow disease progression and treatment would be beneficial. These markers could also be further studied for implication in the pathogenesis of aneurysm development.

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