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Project

Understanding how neutrophil extracellular traps (NETs) contribute to vulnerability of the ageing heart

Ageing is a major risk factor for heart failure, which is a leading cause of mortality worldwide. Which factors and processes render the elderly heart more vulnerable to additional stressors, like hypertension, remains unclear. Growing evidence suggests that the hearts’ resident cells (cardiomyocytes and fibroblasts) are not the sole contributors to this increasing vulnerability. With ageing, the immune system undergoes a shift from adaptive to innate immunity. In addition, there is a constant low-grade level of inflammation in the ageing heart. Our interest lies in a key player in inflammatory and immune responses: the neutrophil. These innate immune cells play an important role not only in early phase responses to infections and tissue damage but also have long-term effects via their influence on other immune players that are recruited at later stages. One of their defense mechanisms is the formation of neutrophil extracellular traps (NETs), which involves releasing a web of DNA fibers lined with toxic proteins and histones. When this process becomes excessively activated it can be detrimental to the surrounding tissue and enhance the pro-inflammatory environment. Hereby, they contribute to downstream stress responses like scar formation, which promotes progression to heart failure. At this stage, the heart is no longer able to properly pump blood to the rest of the body. Absence of this NET response in genetically modified preclinical models reduces signs of cardiac ageing and preserves heart function in aged animals. We will study these older animals along with their younger counterparts and identify differences in expression, functionality and physiology of the different cell types involved in cardiac aging. By comparing neutrophil responses to cardiac stressors in aged vs. young preclinical models, we aim to understand how this protective phenotype is established and how neutrophils and NETs contribute to vulnerability of the ageing heart. We will also identify other mediators of the immune system that are involved in the stress response and could accelerate or slow down heart failure. New insights in these mechanisms contributing to cardiac vulnerability could guide future developments of therapeutic strategies to expand health span and ameliorate quality of life of the elderly.

Date:1 Oct 2022 →  Today
Keywords:Neutrophil, Cardiac aging, Heart failure, Neutrophil extracellular traps
Disciplines:Inflammation, Cardiology
Project type:PhD project