Research team
Investigating SERPINA3 as target and predictive marker in chemotherapy-induced cardiovascular dysfunction.
Abstract
Recently, we discovered upregulation of a certain protein (SERPINA3) in a mouse model of chemotherapy-related cardiac dysfunction (CTRCD). This observation was confirmed by higher SERPINA3 plasma levels in patients with CTRCD. Growing evidence points to SERPINA3 as prognostic marker in cardiovascular disease, yet its role in cardiovascular pathology is poorly understood. The current proposal will shed light on the role of SERPINA3 in CTRCD, as well as its possible use as predictive marker. A bench to bedside approach will be implemented taking advantage of an established experimental mouse model of CTRCD induced by doxorubicin, combined with a prospective clinical trial in anthracycline-treated lymphoma patients. First, SERPINA3 knockout and wild type mice will be subjected to CTRCD to investigate the role of SERPINA3 in cardiac and vascular dysfunction. More specifically, the role of SERPINA3 on inflammatory pathways, as well as on ferroptosis will be evaluated. The in vivo study will be complemented with in vitro experiments with primary endothelial cells (EC), cardiomyocytes and vascular smooth muscle cells. A second part involves a translational in vivo study aimed to evaluate the effect of cardioprotective (heart failure, HF) drugs (i.e., an ACE-inhibitor+betablocker and an SGLT2-inhibitor) in the CTRCD mouse model with specific focus on SERPINA3 and EC-function. Finally, a third part involves a prospective, multicentric, observational study in lymphoma patients treated with anthracycline-based chemotherapy to investigate plasma SERPINA3 and retinal EC-function during CTRCD and its treatment with HF drugs. Ultimately, this project will contribute to the validation of SERPINA3 as predictive marker and will provide proof of concept of SERPINA3 as therapeutic strategy.Researcher(s)
- Promoter: Guns Pieter-Jan
- Co-promoter: Franssen Constantijn
Research team(s)
Project type(s)
- Research Project
Immune Checkpoint Inhibitors induce endothelial inflammation as first step in cardiovascular side effects
Abstract
Immune checkpoint inhibitors (ICI) have revolutionized oncological care, but cardiovascular immune related adverse events are feared. There is growing evidence suggesting that ICI accelerate atherosclerosis or even lead to increased risk for acute coronary syndromes. The current proposal studies the effects of ICI on the cardiovascular system, hypothesizing that ICI induce endothelial inflammation and dysfunction. VCAM-1 is expected to be key in these processes and could function as a potential target in future project proposals. Mice (C57/Bl6 and ApoE-/-) will be treated with ICI for one week and undergo in vivo functional cardiovascular assessment with echocardiography and pulse wave velocity. Upon sacrifice, ex vivo endothelial function will be studied and inflammatory markers will be analyzed. The purpose of this proposal is to demonstrate early endothelial inflammation and VCAM-1 upregulation after ICI treatment. This hypothesis was incorporated in previous grant proposals (FWO Junior Project, Stand up against Cancer, Foundation against Cancer) and was positively reviewed and considered relevant and novel, but preliminary data were absent. With this BOF Small Research Grant, preliminary data will be obtained to apply for further funding and start this new line of research within GENCOR.Researcher(s)
- Promoter: Franssen Constantijn
Research team(s)
Project type(s)
- Research Project