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.
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