Anton Horrevoets More on research

Vascular inflammation and remodelling

The remodeling of coronary arteries preceding and following acute myocardial infarction is a pivotal process in this pathology and determines long term outcome after Primary Coronary Intervention (PCI, Dotter). Remodeling is primarily governed by changes in blood flow, as sensed by the endothelial cells that line all vessels. Next, inflammatory cells of the innate immune system are locally recruited to effectuate the vascular remodeling process through the production of matrix degrading enzymes, inflammatory mediators and growth promoting factors. During acute events, there is a differential recruitment of different cells from the bone-marrow, including monocyte subtypes and progenitor/stem cells. All these processes are heavily influenced by the known risk factors for cardiovascular disease, like high cholesterol level and diabetes mellitus. Furthermore, the individual genetic/genomic makeup of patients has a large effect on both cellular responses and clinical outcome. We employ 'functional genomics' (see research line Tineke van der Pouw Kraan), to identify potential pivotal players in both pathological and beneficial arterial and cardiac remodeling, both in laboratory systems and in specific patient cohorts from the Diabetes Center and the department of Cardiology. Three specific research lines cluster our research: 1. Endothelial cells and biomechanics as triggers of vascular remodeling; 2. Innate immune cells as mediators of vascular remodeling and 3. Innate immune cells as modulators of cardiac remodeling and repair.

1. Endothelial cells and biomechanics as triggers of vascular remodeling

This most basic part of our research targets the molecular processes that enable endothelial cells to convert biomechanical forces from altered blood flow into signaling cues to vessel wall and immune cells to direct vascular remodeling. A key transcription factor to relay such signals was identified by us, the transcription factor KLF2, which is currently the focus of our research, at mechanistic level and as target for small molecule intervention in relation to systemic risk factors for cardiovascular diseases like hyperlipidemia and diabetes.

2. Innate immune cells as mediators of vascular remodeling

This translational research targets the differential response of individual cardiology patients to chronic partial obstruction of coronary arteries. Patients that are able to induce a substantial cardiac vessel remodeling through collateral vessel bypasses, show a much improved chance of surviving a myocardial infarction, and resistance to chronic heart failure. Differential responses of circulating immune cells and progenitor cells represent these individual differences at the molecular level, and using a bedside-to-bench approach we have identified and validated several novel molecular targets, like Interferon-beta and Galectin-2, that might be used for therapy in patients with insufficient collateralization.

3. Innate immune cells as modulators of cardiac remodeling and repair

The extent of irreversible damage to the myocardial tissue developing in days surrounding the acute myocardial infarction determines for a large part clinical outcome and progression to lethal heart failure. Innate immune cells play a pivotal role in both causing the damage but also in repairing damaged cardiac tissue and vasculature. Again, large differences between patients could be related to molecular profiles of the innate immune cells and/or their differential recruitment, providing clues for interventions in these processes during the primary Percutaneous Coronary Intervention (Dotteren).